Substituted heterocyclic derivatives useful as antidiabetic and antiobesity agents and method

ABSTRACT

Compounds are provided which are useful as antidiabetic agents and antiobesity agents and have the structure  
                 
 
     wherein m is 0, 1 or 2; n is 0, 1 or 2;  
     Q is C or N;  
     A is (CH 2 ) x  where x is 1 to 5, or A is (CH 2 ) x   1  where x 1  is 1 to 5 with an alkenyl bond or an alkynyl bond embedded anywhere in the chain, or A is —(CH 2 ) x   2 —O—(CH 2 ) x   3  where x 2  is 0 to 5 and X 3  is 0 to 5, provided that at least one of x 2  and X 3  is other than 0;  
     B is a bond or is (CH 2 ) x   4  where X 4  is 1 to 5;  
     X is CH or N;  
     X 2  is C, N, O or S;  
     X 3  is C, N, O or S;  
     X 4  is C, N, O or S;  
     X 5  is C, N, O or S;  
     X 6  is C, N, O or S;  
     provided that at least one of X 2 , X 3 , X 4  X 5  and X 6  is N; and at least one of X 2 , X 3 , X 4  X 5  and X 6  is C, and specifically excluding the structure(s) as shown below:  
                 
 
     where X 2 ═N, X 3 ═C, X 4 =O or S, Z=O or a bond  
     R 1  is H or alkyl;  
     R 2  is H, alkyl, alkoxy, halogen, amino or substituted amino or cyano;  
     R 2a , R 2b  and R 2c  may be the same or different and are selected from H, alkyl, alkoxy, halogen, amino or substituted amino or cyano; and R 3  and Y are as defined herein, which compounds are useful in treating diabetes and obesity.

[0001] This application claims priority from U.S. ProvisionalApplication No. 60/394,553, filed Jul. 9, 2002 which is incorporatedherein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to novel substituted heterocyclicderivatives which modulate blood glucose levels, triglyceride levels,insulin levels and non-esterified fatty acid (NEFA) levels, and thus areparticularly useful in the treatment of diabetes and obesity, and to amethod for treating diabetes, especially Type 2 diabetes, as well ashyperglycemia, hyperinsulinemia, hyperlipidemia, obesity,atherosclerosis and related diseases employing such substitutedheterocyclic derivatives alone or in combination with anotherantidiabetic agent and/or a hypolipidemic agent and/or other therapeuticagents.

DESCRIPTION OF THE INVENTION

[0003] In accordance with the present invention, substitutedheterocyclic derivatives are provided which have the structure I

[0004] wherein m is 0, 1 or 2; n is 0, 1 or 2;

[0005] Q is C or N;

[0006] A is (CH₂)_(x) where x is 1 to 5, or A is (CH₂)_(x) ¹ where x¹ is1 to 5 with an alkenyl bond or an alkynyl bond embedded anywhere in thechain, or A is —(CH₂)_(x) ²—O—(CH₂)_(x) ³— where x² is 0 to 5 and x³ is0 to 5, provided that at least one of x² and x³ is other than 0;

[0007] B is a bond or is (CH₂)_(x) ⁴ where X⁴ is 1 to 5;

[0008] X is CH or N;

[0009] X₂ is C, N, O or S;

[0010] X₃ is C, N, O or S;

[0011] X₄ is C, N, O or S;

[0012] X₅ is C, N, O or S;

[0013] X₆ is C, N, O or S;

[0014] provided that at least one of X₂, X₃, X₄ X₅ and X₆ is N; and atleast one of X₂, X₃, X₄ X₅ and X₆ is C, and specifically excluding thestructure(s) as shown below:

[0015] where X₂═N, X₃═C, X₄═O or S, Z═O or a bond

[0016] In each of X through X₆, as defined above, C may include CH.

[0017] R¹ is H or alkyl;

[0018] R² is H, alkyl, alkoxy, halogen, amino, substituted amino orcyano;

[0019] R^(2a), R^(2b) and R^(2c) may be the same or different and areselected from H, alkyl, alkoxy, halogen, amino, substituted amino orcyano;

[0020] R³ is selected from H, alkyl, arylalkyl, aryloxycarbonyl,alkyloxycarbonyl, alkynyloxycarbonyl, alkenyloxycarbonyl, arylcarbonyl,alkylcarbonyl, aryl, heteroaryl, cycloheteroalkyl, heteroarylcarbonyl,heteroaryl-heteroarylalkyl, alkylcarbonylamino, arylcarbonylamino,heteroarylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino,heteroaryloxycarbonylamino, heteroaryl-heteroarylcarbonyl,alkylsulfonyl, alkenylsulfonyl, heteroaryloxycarbonyl,cycloheteroalkyloxycarbonyl, heteroarylalkyl, aminocarbonyl, substitutedaminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylalkenyl,cycloheteroalkyl-heteroarylalkyl; hydroxyalkyl, alkoxy,alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl,arylheteroarylalkyl, arylalkylarylalkyl, aryloxyarylalkyl,haloalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl,aryloxyaryloxycarbonyl, arylsulfinylarylcarbonyl, arylthioarylcarbonyl,alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl,heteroaryloxyarylalkyl, aryloxyarylcarbonyl,aryloxyarylalkyloxycarbonyl, arylalkenyloxycarbonyl, arylalkylcarbonyl,aryloxyalkyloxycarbonyl, arylalkylsulfonyl, arylthiocarbonyl,arylalkenylsulfonyl, heteroarylsulfonyl, arylsulfonyl, alkoxyarylalkyl,heteroarylalkoxycarbonyl, arylheteroarylalkyl, alkoxyarylcarbonyl,aryloxyheteroarylalkyl, heteroarylalkyloxyarylalkyl, arylarylalkyl,arylalkenylarylalkyl, arylalkoxyarylalkyl, arylcarbonylarylalkyl,alkylaryloxyarylalkyl, arylalkoxycarbonylheteroarylalkyl,heteroarylarylalkyl, arylcarbonylheteroarylalkyl,heteroaryloxyarylalkyl, arylalkenylheteroarylalkyl, arylaminoarylalkyl,aminocarbonylarylarylalkyl;

[0021] Y is CO₂R⁴ (where R⁴ is H or alkyl, or a prodrug ester) or Y is aC-linked 1-tetrazole, a phosphinic acid of the structureP(O)(OR^(4a))R⁵, (where R^(4a) is H or a prodrug ester, R⁵ is alkyl oraryl) or a phosphonic acid of the structure P(O) (OR^(4a))₂;

[0022] (CH₂)_(x), (CH₂)_(x) ¹, (CH₂)_(x) ², (CH₂)_(x) ³, (CH₂)_(x) ⁴,(CH₂)_(m), and (CH₂)_(n) may be optionally substituted with 1, 2 or 3substituents;

[0023] including all stereoisomers thereof, prodrug esters thereof, andpharmaceutically acceptable salts thereof.

[0024] Examples of

[0025] which are present in the compounds of the invention include, butare not limited to,

[0026] as the five-membered rings covered under the definition ofheteroaryl set out hereinafter,

[0027] preferably

[0028] Preferred are compounds of formula I of the invention having thestructure IA

[0029] where X is CH

[0030] More preferred are compounds of formula I of the invention havingthe structure IB

[0031] In the above compounds, it is most preferred that R^(2a), R^(2b)and R^(2c) are each H; R¹ is alkyl, preferably CH₃; x² is 1 to 3; R² isH; m is 0 or (CH₂)_(m) is CH₂ or CHOH or CH-alkyl, X₂, X₃, X₄, X₅ and X₆represent a total of 1, 2 or 3 nitrogens; (CH₂)_(n) is a bond or CH₂, R³is arylalkyloxycarbonyl, arylheteroarylalkyl, aryloxyarylalkyl,arylalkyl, aryloxycarbonyl, haloaryloxycarbonyl, alkoxyaryloxycarbonyl,alkylaryloxycarbonyl, aryloxyaryloxycarbonyl, heteroaryloxyarylalkyl,heteroaryloxycarbonyl, aryloxyarylcarbonyl, arylalkenyloxycarbonyl,cycloalkylaryloxycarbonyl, arylalkylarylcarbonyl,heteroaryl-heteroarylalkyl, cycloalkyloxyaryloxycarbonyl,heteroaryl-heteroarylcarbonyl, arylalkylsulfonyl, arylalkenylsulfonyl,alkoxyarylalkyl, arylthiocarbonyl, cycloheteroalkylalkyloxycarbonyl,cycloheteroalkyloxycarbonyl, or polyhaloalkylaryloxycarbonyl, which maybe optionally substituted, more preferably alkoxyaryloxycarbonyl.

[0032] Preferred compounds of the invention include the following:

[0033] In addition, in accordance with the present invention, a methodis provided for treating diabetes, especially Type 2 diabetes, andrelated diseases such as Type I diabetes, insulin resistance,hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids orglycerol, hyperlipidemia, obesity, hypertriglyceridemia, inflammation,Syndrome X, diabetic complications, dysmetabolic syndrome,atherosclerosis, and related diseases wherein a therapeuticallyeffective amount of a compound of structure I is administered to apatient in need of treatment.

[0034] In addition, in accordance with the present invention, a methodis provided for treating early malignant lesions (such as ductalcarcinoma in situ of the breast and lobular carcinoma in situ of thebreast), premalignant lesions (such as fibroadenoma of the breast andprostatic intraepithelial neoplasia (PIN), liposarcomas and variousother epithelial tumors (including breast, prostate, colon, ovarian,gastric and lung), irritable bowel syndrome, Crohn's disease, gastriculceritis, and osteoporosis and proliferative diseases such aspsoriasis, wherein a therapeutically effective amount of a compound ofstructure I is administered to a patient in need of treatment.

[0035] In addition, in accordance with the present invention, a methodis provided for treating diabetes and related diseases as defined aboveand hereinafter, wherein a therapeutically effective amount of acombination of a compound of structure I and another type antidiabeticagent and/or a hypolipidemic agent, and/or lipid modulating agent and/orother type of therapeutic agent, is administered to a human patient inneed of treatment.

[0036] In the above method of the invention, the compound of structure Iwill be employed in a weight ratio to the antidiabetic agent (dependingupon its mode of operation) within the range from about 0.01:1 to about100:1, preferably from about 0.5:1 to about 10:1.

[0037] The conditions, diseases, and maladies collectively referenced toas “Syndrome X” or Dysmetabolic Syndrome (as detailed in Johanson, J.Clin. Endocrinol. Metab., 1997, 82, 727-734, and other publications)include hyperglycemia and/or prediabetic insulin resistance syndrome,and is characterized by an initial insulin resistant state generatinghyperinsulinemia, dyslipidemia, and impaired glucose tolerance, whichcan progress to Type II diabetes, characterized by hyperglycemia, whichcan progress to diabetic complications.

[0038] The term “diabetes and related diseases” refers to Type IIdiabetes, Type I diabetes, impaired glucose tolerance, obesity,hyperglycemia, Syndrome X, dysmetabolic syndrome, diabetic complicationsand hyperinsulinemia.

[0039] The conditions, diseases and maladies collectively referred to as“diabetic complications” include retinopathy, neuropathy andnephropathy, and other known complications of diabetes.

[0040] The term “other type(s) of therapeutic agents” as employed hereinrefers to one or more antidiabetic agents (other than compounds offormula I), one or more anti-obesity agents, and/or one or morelipid-lowering agents, one or more lipid modulating agents (includinganti-atherosclerosis agents), and/or one or more antiplatelet agents,one or more agents for treating hypertension, one or more anti-cancerdrugs, one or more agents for treating arthritis, one or moreanti-osteoporosis agents, one or more anti-obesity agents, one or moreagents for treating immunomodulatory diseases, and/or one or more agentsfor treating anorexia nervosa.

[0041] The term “lipid-modulating” agent as employed herein refers toagents which lower LDL and/or raise HDL and/or lower triglyceridesand/or lower total cholesterol and/or other known mechanisms fortherapeutically treating lipid disorders.

DETAILED DESCRIPTION OF THE INVENTION

[0042] The compounds of the formula I of the present invention may beprepared according to the following general synthetic schemes, as wellas relevant published literature procedures that are used by one skilledin the art. Exemplary reagents and procedures for these reactions appearhereinafter and in the working Examples. Protection and deprotection inthe Schemes below may be carried out by procedures generally known inthe art (see, for example, T. W. Greene & P. G. M. Wuts, ProtectingGroups in Organic Synthesis, 3^(rd) Edition, 1999 [Wiley]).

[0043] Scheme 1 describes a general synthesis of the amino acidsdescribed in this invention. An alcohol 1 (R⁵(CH₂)_(x) ²OH) is coupledwith a hydroxy aryl- or heteroaryl-aldehyde 2 (preferably 3- or4-hydroxybenzaldehyde) under standard Mitsunobu reaction conditions(e.g. Mitsunobu, O., Synthesis, 1981, 1). The resulting aldehyde 3 isthen subjected to reductive amination using procedures known in theliterature (e.g. Abdel-Magid et al, J. Org. Chem. 1996, 61, 3849) withan α-amino ester hydrochloride 4. PG in Scheme 1 denotes a preferredcarboxylic acid-protecting group, such as a methyl or tert-butyl ester.The resulting secondary amino-ester 5 is then subjected to a secondreductive amination using methods known in the literature (e.g.Abdel-Magid et al, J. Org. Chem. 1996, 61, 3849) with an R^(3a) aldehyde6. Final deprotection of the carboxylic acid ester under standardconditions known in the literature (reference: Greene et al supra)utilizing basic conditions (for methyl esters) or acidic conditions (fortert-butyl esters) then furnishes the desired amino acid products II.

[0044] An alternative route to the aldehyde 3 is shown in Scheme 1A.Alcohol 1 (R⁵(CH₂)_(x)OH) is treated with methanesulfonyl chloride togive the corresponding mesylate 7. The mesylate 7 is then alkylatedunder standard basic conditions with a hydroxyaryl or hydroxyheteroarylaldehyde 2 to furnish the aldehyde 3.

[0045] A route to the amino acids III is shown in Scheme 2. Thesecondary amine-ester 5 is deprotected under standard conditions (basicconditions if the protecting group (PG) is methyl; acidic conditions ifPG is tert-butyl; ref. Greene et al supra) to furnish the correspondingamino acid 8. Reductive amination with aldehyde 9 under analogousconditions as described in Scheme 1 provides the desired tertiary aminoacid products III.

[0046] Alternatively, as shown in Scheme 3, reaction of the secondaryamine-ester 5 with an alkylating agent 10 (with an appropriate leavinggroup (LG) such as halide, mesylate, or tosylate) under standardconditions followed by deprotection of the carboxylic acid ester 11provides the desired tertiary amino acids III.

[0047] As shown in Scheme 4, the tertiary amino acid III may also beassembled through reductive amination first of the R^(3a) aldehyde 12with an appropriate amine ester hydrochloride 4. The resulting secondaryamine-ester 13 then is subjected to reductive amination with appropriatealkyl, aryl or heteroaryl aldehydes 3 (as in Scheme 1) followed bydeprotection of the carboxylic acid ester to give the desired amino acidanalogs III.

[0048] An alternative general synthesis of amino acid analogs II isshown in Scheme 5. A hydroxyaryl or heteroaryl aldehyde 2 is subjectedto the usual reductive amination conditions with an appropriateamine-ester hydrochloride 4. The resulting secondary amine-ester 14 isfunctionalized, in this case by a second reductive amination withaldehyde 6 to furnish the corresponding hydroxy tertiary amine-ester 15.Phenol 15 now undergoes a Mitsunobu reaction with a preferred alcohol 1(R⁵—(CH₂)_(n)OH) which is followed by the deprotection of the product,ester 16, to furnish the desired amino acid analogs II.

[0049] Scheme 6 illustrates the synthesis of the carbamate-acid analogsIV. The secondary amine-ester 5 can be reacted with appropriatechloroformates 17 under standard literature conditions (optimally inCH₂Cl₂ or CHCl₃ in the presence of a base such as Et₃N) to furnish thecorresponding carbamate-esters. The requisite analogs IV are thenobtained after deprotection of the carbamate-ester. Alternatively, thesecondary amine-ester 5 can be reacted with phosgene to generate thecorresponding carbamyl chloride 18. This carbamyl chloride intermediate18 can be reacted with R^(3a)—OH (19; optimally substituted phenols) toafford the corresponding carbamate-acids IV after deprotection.

[0050] The secondary amine-ester 5 can be functionalized withsubstituted aryl or aliphatic carboxylic acids 20, under standardpeptide coupling conditions, as illustrated in Scheme 7. The amidebond-formation reactions are conducted using standard peptide couplingprocedures known in the art. Optimally, the reaction is conducted in asolvent such as DMF at 0° C. to RT using1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDAC or EDCI or WSC),1-hydroxybenzotriazole (HOBT) or 1-hydroxy-7-azabenzotriazole (HOAT) anda base, e.g. diisopropylethylamine, N-methyl morpholine ortriethylamine. Deprotection of the amide-ester then furnishes thedesired amide-acid analogs V.

[0051] The secondary amine-ester 5 can also be reacted with aliphatic oraryl isocyanates 21 to provide the corresponding urea-esters.Deprotection of this product provides the desired urea-acid analogs VI,as shown in Scheme 8. Alternatively, as shown in Scheme 9, the carbamylchloride intermediate 18 described in Scheme 6 can be reacted withappropriate primary or secondary aliphatic or aryl amines 23 and 23 inthe presence of a tertiary amine (e.g. Et₃N) to furnish tri- ortetrasubstituted urea-acid analogs VII or VIII after deprotection of theester.

[0052] The secondary amine-ester 5 can also be reacted with appropriatesulfonyl chlorides 24 under standard literature conditions (optimally inthe presence of a base such as pyridine, either neat or using chloroformas a co-solvent), followed by deprotection, to provide the correspondingsulfonamide-acids IX, as shown in Scheme 10.

[0053] The different approaches to the preparation of the preferredracemic α-alkylbenzyl carbamate-acid and amino acid analogs X and XIrespectively are exemplified in synthetic Schemes 11 and 12. In Scheme11 a substituted aryl nitrile (with a suitable aromatic heterocycle RSalready appended) is treated with an appropriate organometallic reagent(e.g. a Grignard reagent R¹⁰MgX 26 or an organolithium reagent R¹⁰Li)under standard conditions to give the corresponding imine intermediate,which is immediately reduced (e.g. with LiAlH₄) to give thecorresponding primary amine 27. Amine 27 is then reacted with anappropriately substituted α-halo-ester 28 to provide the correspondingα-amine-ester 29. It will be understood that in the amine-ester 29, themoiety

[0054] does not necessarily represent two repeating units.

[0055] Acylation of the amine-ester 29 with an appropriately substitutedaryl or heteroaryl chloroformates 17 followed by deprotection providesthe racemic carbamate-acid analogs X. Reductive amination of alkylbenzylamine-ester 29 with aryl aldehyde 6 followed by deprotection providesthe racemic amino-acid analogs XI.

[0056] Alternatively (as shown in Scheme 12), a protected aryl orheteroaryl nitrile 30 is treated with an appropriate organometallicreagent (e.g. a Grignard reagent R¹⁰MgX 26) to give the correspondingimine intermediate, which is immediately reduced (e.g. with LiAlH₄) togive the corresponding primary amine 31. This amine is then reacted withan appropriately substituted α-halo-ester 28 to give the correspondingα-amine-ester 32. This intermediate 32 can then be acylated with anappropriately substituted aryl or heteroaryl chloroformate 17 to providethe corresponding carbamate-ester, whose phenolic functionality is thendeprotected to provide the key intermediate phenol 33. Alkylation of thephenol 33 with a halide or mesylate 7 followed by deprotection providesthe racemic carbamate-acid analogs X. An analogous sequence, whichinvolves reductive amination of the secondary amino-ester 32 with anaryl or heteroaryl aldehyde 6, then selective phenol deprotection,alkylation with mesylate 7 and a final deprotection, provides theracemic amino acid analogs XI.

[0057] A synthesis of chiral carbamate analogs XII and amino acidanalogs XIII is shown in Scheme 13. Asymmetric reduction (e.g. using theCorey oxazaborolidine reduction protocol; review: E. J. Corey & C.Helal, Angew. Chem. Int. Ed. Engl., 1998, 37, 1986-2012) of thearyl-ketone 34 provides each of the two desired enantiomeric alcohols 35(although only one enantiomer is represented in the scheme). Treatmentof the chiral alcohol 35 with azide in a Mitsunobu-like reaction (ref:A. S. Thompson et. al., J. Org. Chem. 1993, 58, 5886-5888) gives thecorresponding chiral azide (with inverted stereochemistry from thestarting alcohol). This azide is then reduced to the amine 36 bystandard methods (e.g. hydrogenation or Ph₃P/THF/H₂O). Treatment of thechiral amine 36 with an α-halo-ester 28 provides the secondaryamine-ester 37. Acylation of amino-ester 36 with an aryl or heteroarylchloroformate 17 followed by deprotection provides the chiralcarbamate-acid analogs XII (which may be either enantiomer dependingupon the stereochemistry of 36). Reductive amination of alkylamino-ester 37 with aryl aldehydes 6 followed by deprotection providesthe chiral amino-acid analogs XIII (which may be either enantiomerdepending upon the stereochemistry of 36).

[0058] An alternative synthesis of analogs XII and XIII is shown inScheme 14. An appropriately protected oxyaryl ketone 38 undergoesasymmetric reduction to give the chiral alcohol 39. This is converted tothe chiral amine 40 via the identical sequence as in Scheme 13 (via thechiral azide). Treatment of the chiral amine 40 with an ester 28(LG=halogen or mesylate) gives the corresponding secondary amino-ester41. Acylation of 41 with an aryl or heteroaryl chloroformate 17 providesthe corresponding carbamate-ester. Selective deprotection furnishes thefree phenol carbamate-ester 42. Alkylation of the phenol 42 with ahalide or mesylate 7 followed by deprotection provides the chiralcarbamate-acid analogs XII. An analogous sequence which involvesreductive amination of the secondary amine-ester 41 with an aryl orheteroaryl aldehyde 6, then selective deprotection, alkylation with 7and a final deprotection, provides the chiral amino acid analogs XIII.It will be appreciated that either the (R)- or (S)-enantiomer of X or XImay be synthesized in Schemes 13 and 14, depending upon the chirality ofthe reducing agent employed.

[0059] A preferred alternative asymmetric synthesis of carbamate-acidsXII is shown in Scheme 15. Protection of a chiral amine 43 (with thephenol differently protected), preferably as a carbamate, providesintermediate 44. Selective removal of the phenolic protecting group of44 provides the free phenol 45. Alkylation of phenol 45 with themesylate 7 furnishes the protected amine 46. Deprotection of the amineof 45 then furnishes the key intermediate, the primary amine-ester 36,which then undergoes alkylation with a α-halo-ester 28 in the presenceof base to provide the secondary amine 37. Reaction of amine 37 with achloroformate 17 provides the chiral carbamate acid analogs XII.

[0060] A preferred asymmetric synthesis of analogs XIV and XV is shownin Scheme 16. The aldehyde 3 is subjected to standard Wittig reactionconditions (ref: Preparation of Alkenes, a Practical Approach, J. J.Williams, Ed., Chapter 2, pp 19-58) to furnish the alkene 47. Asymmetricaminohydroxylation according to known literature procedures (ref:O'Brien, P., Angew. Chem. Int. Ed., 1999, 38, 326 and Reddy, K. L., andSharpless, K. B., J. Am. Chem. Soc., 1998, 120, 1207) furnishes thedesired amino-alcohol 48 as a single enantiomer. It is understood thatthis reaction can produce either enantiomer (of which only one is shownhere). Selective protection of the amine 48 provides the alcohol 49.Alcohol 49 is then converted by standard methods to the intermediate 50,which contains a suitable leaving group (either a halide or a mesylate)for the subsequent cuprate displacement reaction. Reaction of anappropriate higher-order cuprate 51 (ref: L. A. Paquette, Ed., OrganicReactions, 1992, Vol. 41, J. Wiley & Sons) with the protected aminesubstrate 50 provides the coupled, protected amine 52. Deprotection ofthe amine functionality of 52, followed by reaction with an ester 28(LG=halogen or mesylate), furnishes the corresponding secondaryamino-ester 53. Acylation of amine 53 with an aryl or heteroarylchloroformate 17 provides the corresponding carbamate-ester, which isthen deprotected to furnish the carbamate-acid analogs XIV.

[0061] Alternatively, reductive amination of amine 53 with an aldehyde 6followed by deprotection provides the tertiary amino acid analogs XV.

[0062] The synthesis of carbon-linked analogs are shown in Schemes17-19. Scheme 17 describes a general synthesis of the acetylene-linkedacids XVI and the alkyl-linked acids XVII. A halo-substituted arylaldehyde 54 (preferably iodide or bromide) is subjected to reductiveamination using procedures known in the literature (e.g. Abdel-Magid etal, J. Org. Chem. 1996, 61, 3849) with an α-amino acid esterhydrochloride V. The resulting secondary amino-ester 55 is then reactedwith an aryl or heteroaryl chloroformate 17 in the presence of anappropriate base (e.g. pyridine or triethylamine) to furnish thecorresponding halo-aryl carbamate-ester 56. Aryl halide 56 is thenreacted with an appropriate heteroaryl (R⁵)-substituted acetylene 57 inthe presence of an appropriate palladium catalyst (e.g. (Ph₃P)₂PdCl₂/anda copper (I) salt (e.g. CuI) in a Sonogashira coupling reaction (ref:Organocopper Reagents, a Practical Approach, R. J. K. Taylor, Ed.,Chapter 10, pp 217-236, Campbell, I. B., Oxford University Press, 1994)to furnish the key intermediate, arylacetylene 58. The arylacetyleneester 58 is deprotected to provide the corresponding arylacetylene acidanalogs XVI. The acetylene moiety of 58 can be reduced by standardmethods (e.g. hydrogenation, ref: M. Hudlicky, Reductions in OrganicChemistry, 2^(nd) Edition, ACS, 1996, Chapter 1) to furnish thecorresponding fully saturated alkyl aryl carbamate esters, which arethen deprotected to give the alkyl aryl carbamate acid analogs XVII.

[0063] Stereoselective reduction of the acetylene ester 58 by standardmethods (e.g. Lindlar's catalyst; ref: Preparation of Alkenes, APractical Approach, J. J. Williams, Ed., Chapter 6, pp 117-136, OxfordUniversity Press, 1996) can be achieved to provide the correspondingcis-alkenyl aryl carbamate-ester, which is then deprotected to furnishthe Z-alkenyl aryl carbamate acid analogs XVIII (Scheme 18).Alternatively, this sequence can be reversed, i.e. the initial stepbeing the deprotection of acetylenic ester 58 to the acetylenic acid,followed by stereoselective reduction of the acetylene moiety to providethe Z-alkene-acid analogs XVIII.

[0064] The corresponding trans-alkenyl aryl carbamate acids XIX aresynthesized according to the general route in Scheme 19. A heteroaryl(R⁵)-acetylene 57 is halogenated under standard conditions (ref: Boden,C. D. J. et al., J. Chem. Soc. Perkin Trans. 1,1996, 2417; or Lu, W. et.al., Tetrahedron Lett. 1998, 39, 9521) to give the correspondinghalo-acetylene, which is then converted to the correspondingtrans-alkenyl stannane 59 (ref: Boden, C. D. J., J. Chem. Soc., PerkinTrans. 1,1996, 2417). This aryl- or heteroaryl-substituted trans-alkenylstannane 59 is then coupled with the halo-aryl carbamate ester 56 understandard Stille coupling conditions (ref: Farina, V. et. al., “TheStille Reaction”, Organic Reactions, 1997, 50, 1) to furnish thecorresponding trans-alkenyl aryl carbamate ester 60. Thiscarbamate-ester is then deprotected under standard conditions to givethe desired trans-alkenyl aryl carbamate acid analogs XIX.

[0065] In Scheme 20, treatment of a suitably protected halo-arylcarbamate-ester 56 with a metallating agent (e.g. isopropyl magnesiumbromide, reference: P. Knochel et al., Synthesis, 2002, 565-569)furnishes the corresponding arylmagnesium reagent, which is then reactedwith formaldehyde to provide benzyl alcohol 61. Treatment of alcohol 61with mesylate VIII in the presence of base provides the correspondingether-carbamate ester, which is then deprotected to furnish theether-acid XX of the invention.

[0066] In Scheme 21, treatment of a suitably protected halo-arylcarbamate-ester 56 with an appropriate vinyl tin reagent (e.g.tributylvinyltin) under Stille coupling conditions (reference: Farina,V., Krishnamurthy, V., and Scott, W. J., Organic Reactions, 1997, 50, 1)provides the corresponding vinyl intermediate, which can then undergohydroboration (e.g. borane-THF) to give the alcohol 62. Treatment ofalcohol 62 with mesylate VIII in the presence of base provides thecorresponding ether carbamate-ester, which is then deprotected toprovide the ether acid XXI of the invention.

[0067] The synthesis of N-aryl acids XXII of the invention is shown inScheme 22. Reductive amination of protected phenol-aldehyde 2 with anappropriate aniline 63 (or other heteroarylamine) provides thesubstituted aromatic amine intermediate 64. N-alkylation of the aromaticamine 64 with an appropriate halo-substituted ester 65 in the presenceof base (e.g. sodium hexamethyldisilazide) provides the N-aryl (orheteroaryl) ester 66. Deprotection of the phenol of amino-ester 66provides free phenol 67, which then undergoes Mitsunobu reaction (e.g.using cyanomethylene tributylphosphorane) With an appropriate alcohol 1to provide the alkylated phenol N-aryl amino-ester 68. Deprotection ofthe ester 68 provides N-aryl (or N-heteroaryl) acids XXII of theinvention. Alternatively, phenol 67 can be alkylated with mesylate 7 inthe presence of base (e.g. K₂CO₃) followed by acid deprotection to alsoprovide N-aryl (or N-heteroaryl) acids XXII of the invention.

[0068] In this and the following Reaction Schemes:

[0069] Alternative Scheme 1A for Preparing Aldehyde IV

[0070] Unless otherwise indicated, the term “lower alkyl”, “alkyl” or“alk” as employed herein alone or as part of another group includes bothstraight and branched chain hydrocarbons, containing 1 to 20 carbons,preferably 1 to 10 carbons, more preferably 1 to 8 carbons, in thenormal chain, and may optionally include an oxygen or nitrogen in thenormal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like as well as such groupsincluding 1 to 4 substituents such as halo, for example F, Br, Cl or Ior CF₃, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl, arylalkyl,arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy,amino, hydroxy, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy,cycloheteroalkyl, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl,heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl and/oralkylthio and/or any of the R³ groups.

[0071] Unless otherwise indicated, the term “cycloalkyl” as employedherein alone or as part of another group includes saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl andtricyclicalkyl, containing a total of 3 to 20 carbons forming the rings,preferably 3 to 10 carbons, forming the ring and which may be fused to 1or 2 aromatic rings as described for aryl, which include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyland cyclododecyl, cyclohexenyl,

[0072] any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, amino, nitro, cyano, thiol and/or alkylthio and/orany of the substituents for alkyl.

[0073] The term “cycloalkenyl” as employed herein alone or as part ofanother group refers to cyclic hydrocarbons containing 3 to 12 carbons,preferably 5 to 10 carbons and 1 or 2 double bonds. Exemplarycycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, cyclohexadienyl, and cycloheptadienyl, which may beoptionally substituted as defined for cycloalkyl.

[0074] The term “cycloalkylene” as employed herein refers to a“cycloalkyl” group which includes free bonds and thus is a linking groupsuch as

[0075] and the like, and may optionally be substituted as defined abovefor “cycloalkyl”.

[0076] The term “alkanoyl” as used herein alone or as part of anothergroup refers to alkyl linked to a carbonyl group.

[0077] Unless otherwise indicated, the term “lower alkenyl” or “alkenyl”as used herein by itself or as part of another group refers to straightor branched chain radicals of 2 to 20 carbons, preferably 2 to 12carbons, and more preferably 1 to 8 carbons in the normal chain, whichinclude one to six double bonds in the normal chain, and may optionallyinclude an oxygen or nitrogen in the normal chain, such as vinyl,2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl,3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl,4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and thelike, and which may be optionally substituted with 1 to 4 substituents,namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl,arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl,alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol,alkylthio and/or any of the substituents for alkyl set out herein.

[0078] Unless otherwise indicated, the term “lower alkynyl” or “alkynyl”as used herein by itself or as part of another group refers to straightor branched chain radicals of 2 to 20 carbons, preferably 2 to 12carbons and more preferably 2 to 8 carbons in the normal chain, whichinclude one triple bond in the normal chain, and may optionally includean oxygen or nitrogen in the normal chain, such as 2-propynyl,3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl,2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl, 4-dodecynyl and the like, and which may be optionallysubstituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl,alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino,heteroaryl, cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido,arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio, and/or any ofthe substituents for alkyl set out herein.

[0079] The terms “arylalkenyl” and “arylalkynyl” as used alone or aspart of another group refer to alkenyl and alkynyl groups as describedabove having an aryl substituent.

[0080] Where alkyl groups as defined above have single bonds forattachment to other groups at two different carbon atoms, they aretermed “alkylene” groups and may optionally be substituted as definedabove for “alkyl”.

[0081] Where alkenyl groups as defined above and alkynyl groups asdefined above, respectively, have single bonds for attachment at twodifferent carbon atoms, they are termed “alkenylene groups” and“alkynylene groups”, respectively, and may optionally be substituted asdefined above for “alkenyl” and “alkynyl”.

[0082] (CH₂)_(x), (CH₂)_(x) ¹, (CH₂)_(x) ², (CH₂)_(x) ³ (CH₂)_(x) ⁴,(CH₂)_(m) or (CH₂)_(n) includes alkylene, allenyl, alkenylene oralkynylene groups, as defined herein, each of which may optionallyinclude an oxygen or nitrogen in the normal chain, which may optionallyinclude 1, 2, or 3 substituents which include alkyl, alkenyl, halogen,cyano, hydroxy, alkoxy, amino, thioalkyl, keto, C₃-C₆ cycloalkyl,alkylcarbonylamino or alkylcarbonyloxy; the alkyl substituent may be analkylene moiety of 1 to 4 carbons which may be attached to one or twocarbons in the (CH₂)_(x), (CH₂)_(x) ¹, (CH₂)_(x) ², (CH₂)_(x) ³,(CH₂)_(x) ⁴, (CH₂)_(m) or (CH₂)_(n) group to form a cycloalkyl grouptherewith.

[0083] Examples of (CH₂)_(x), (CH₂)_(x) ¹, (CH₂)_(x) ², (CH₂)_(x) ³(CH₂)_(x) ⁴ (CH₂)_(m), (CH₂)_(n), alkylene, alkenylene and alkynyleneinclude

[0084] The term “halogen” or “halo” as used herein alone or as part ofanother group refers to chlorine, bromine, fluorine, and iodine as wellas CF₃, with chlorine or fluorine being preferred.

[0085] The term “metal ion” refers to alkali metal ions such as sodium,potassium or lithium and alkaline earth metal ions such as magnesium andcalcium, as well as zinc and aluminum.

[0086] Unless otherwise indicated, the term “aryl” or the group

[0087] where Q is C, as employed herein alone or as part of anothergroup refers to monocyclic and bicyclic aromatic groups containing 6 to10 carbons in the ring portion (such as phenyl or naphthyl including1-naphthyl and 2-naphthyl) and may optionally include one to threeadditional rings fused to a carbocyclic ring or a heterocyclic ring(such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings

[0088] for example

[0089] and may be optionally substituted through available carbon atomswith 1, 2, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl,trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl,cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy,aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl,aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro,cyano, amino, substituted amino wherein the amino includes 1 or 2substituents (which are alkyl, aryl or any of the other aryl compoundsmentioned in the definitions), thiol, alkylthio, arylthio,heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl,arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino orarylsulfonaminocarbonyl and/or any of the substituents for alkyl set outherein.

[0090] Unless otherwise indicated, the term “lower alkoxy”, “alkoxy”,“aryloxy” or “aralkoxy” as employed herein alone or as part of anothergroup includes any of the above alkyl, aralkyl or aryl groups linked toan oxygen atom.

[0091] Unless otherwise indicated, the term “substituted amino” asemployed herein alone or as part of another group refers to aminosubstituted with one or two substituents, which may be the same ordifferent, such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituentsmay be further substituted with a carboxylic acid and/or any of thesubstituents for alkyl as set out above. In addition, the aminosubstituents may be taken together with the nitrogen atom to which theyare attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl,4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl,4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl,1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy,alkylthio, halo, trifluoromethyl or hydroxy.

[0092] Unless otherwise indicated, the term “lower alkylthio”,“alkylthio”, “arylthio” or “aralkylthio” as employed herein alone or aspart of another group includes any of the above alkyl, aralkyl or arylgroups linked to a sulfur atom.

[0093] Unless otherwise indicated, the term “lower alkylamino”,“alkylamino”, “arylamino”, or “arylalkylamino” as employed herein aloneor as part of another group includes any of the above alkyl, aryl orarylalkyl groups linked to a nitrogen atom.

[0094] Unless otherwise indicated, the term “acyl” as employed herein byitself or part of another group, as defined herein, refers to an organicradical linked to a carbonyl

[0095] group; examples of acyl groups include any of the R³ groupsattached to a carbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl,heteroaroyl, cycloalkanoyl, cycloheteroalkanoyl and the like.

[0096] Unless otherwise indicated, the term “cycloheteroalkyl” as usedherein alone or as part of another group refers to a 5-, 6- or7-membered saturated or partially unsaturated ring which includes 1 to 2hetero atoms such as nitrogen, oxygen and/or sulfur, linked through acarbon atom or a heteroatom, where possible, optionally via the linker(CH₂)_(p) (where p is 1, 2 or 3), such as

[0097] and the like. The above groups may include 1 to 4 substituentssuch as alkyl, halo, oxo and/or any of of the substituents for alkyl oraryl set out herein. In addition, any of the cycloheteroalkyl rings canbe fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.

[0098] Unless otherwise indicated, the term “heteroaryl” as used hereinalone or as part of another group refers to a 5- or 6-membered aromaticring including

[0099] where Q is N, which includes 1, 2, 3 or 4 hetero atoms such asnitrogen, oxygen or sulfur, and such rings fused to an aryl, cycloalkyl,heteroaryl or cycloheteroalkyl ring (e.g. benzothiophenyl, indolyl), andincludes possible N-oxides. The heteroaryl group may optionally include1 to 4 substituents such as any of the the substituents for alkyl oraryl set out above. Examples of heteroaryl groups include the following:

[0100] and the like.

[0101] The term “cycloheteroalkylalkylyl” as used herein alone or aspart of another group refers to cycloheteroalkyl groups as defined abovelinked through a C atom or heteroatom to a (CH₂)_(p) chain.

[0102] The term “heteroarylalkyl” or “heteroarylalkenyl” as used hereinalone or as part of another group refers to a heteroaryl group asdefined above linked through a C atom or heteroatom to a —(CH₂)_(p)—chain, alkylene or alkenylene as defined above.

[0103] The term “polyhaloalkyl” as used herein refers to an “alkyl”group as defined above which includes from 2 to 9, preferably from 2 to5, halo substituents, such as F or Cl, preferably F, such as CF₃CH₂, CF₃or CF₃CF₂CH₂.

[0104] The term “polyhaloalkyloxy” as used herein refers to an “alkoxy”or “alkyloxy” group as defined above which includes from 2 to 9,preferably from 2 to 5, halo substituents, such as F or Cl, preferablyF, such as CF₃CH₂O, CF₃O or CF₃CF₂CH₂O.

[0105] The term “prodrug esters” as employed herein includes prodrugesters which are known in the art for carboxylic and phosphorus acidesters such as methyl, ethyl, benzyl and the like. Other prodrug esterexamples of R⁴ include the following groups: (l-alkanoyloxy)alkyl suchas,

[0106] wherein R^(a), R^(b) and R^(c) are H, alkyl, aryl or arylalkyl;however, R^(a)O cannot be HO.

[0107] Examples of such prodrug esters R⁴ include

[0108] Other examples of suitable prodrug esters R⁴ include

[0109] wherein R^(a) can be H, alkyl (such as methyl or t-butyl),arylalkyl (such as benzyl) or aryl (such as phenyl); Rd is H, alkyl,halogen or alkoxy, Re is alkyl, aryl, arylalkyl or alkoxyl, and n₁ is 0,1 or 2.

[0110] Where the compounds of structure I are in acid form they may forma pharmaceutically acceptable salt such as alkali metal salts such aslithium, sodium or potassium, alkaline earth metal salts such as calciumor magnesium as well as zinc or aluminum and other cations such asammonium, choline, diethanolamine, lysine (D or L), ethylenediamine,t-butylamine, t-octylamine, tris-(hydroxymethyl)aminomethane (TRIS),N-methyl glucosamine (NMG), triethanolamine and dehydroabietylamine.

[0111] All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one or the R substituents.Consequently, compounds of formula I can exist in enantiomeric ordiastereomeric forms or in mixtures thereof. The processes forpreparation can utilize racemates, enantiomers or diastereomers asstarting materials. When diastereomeric or enantiomeric products areprepared, they can be separated by conventional methods for example,chromatographic or fractional crystallization.

[0112] Where desired, the compounds of structure I may be used incombination with one or more hypolipidemic agents or lipid-loweringagents and/or one or more other types of therapeutic agents includingantidiabetic agents, anti-obesity agents, antihypertensive agents,platelet aggregation inhibitors, and/or anti-osteoporosis agents, whichmay be administered orally in the same dosage form, in a separate oraldosage form or by injection.

[0113] The hypolipidemic agent or lipid-lowering agent which may beoptionally employed in combination with the compounds of formula I ofthe invention may include 1,2,3 or more MTP inhibitors, HMG CoAreductase inhibitors, squalene synthetase inhibitors, fibric acidderivatives, ACAT inhibitors, lipoxygenase inhibitors, cholesterolabsorption inhibitors, ileal Na⁺/bile acid cotransporter inhibitors,upregulators of LDL receptor activity, bile acid sequestrants, and/ornicotinic acid and derivatives thereof.

[0114] MTP inhibitors employed herein include MTP inhibitors disclosedin U.S. Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat. No.5,712,279, U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S. Pat.No. 5,885,983 and U.S. application Ser. No. 09/175,180 filed Oct. 20,1998, now U.S. Pat. No. 5,962,440. Preferred are each of the preferredMTP inhibitors disclosed in each of the above patents and applications.

[0115] All of the above U.S. Patents and applications are incorporatedherein by reference.

[0116] Most preferred MTP inhibitors to be employed in accordance withthe present invention include preferred MTP inhibitors as set out inU.S. Pat. Nos. 5,739,135 and 5,712,279, and U.S. Pat. No. 5,760,246.

[0117] The most preferred MTP inhibitor is9-[4-[4-[[2-(2,2,2-Trifluoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide

[0118] The hypolipidemic agent may be an HMG CoA reductase inhibitorwhich includes, but is not limited to, mevastatin and related compoundsas disclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) andrelated compounds as disclosed in U.S. Pat. No. 4,231,938, pravastatinand related compounds such as disclosed in U.S. Pat. No. 4,346,227,simvastatin and related compounds as disclosed in U.S. Pat. Nos.4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which may beemployed herein include, but are not limited to, fluvastatin, disclosedin U.S. Pat. No. 5,354,772, atorvastatin disclosed in U.S. Pat. Nos.4,681,893, 5,273,995, 5,385,929 and 5,686,104, itavastatin(Nissan/Sankyo's nisvastatin (NK-104)) disclosed in U.S. Pat. No.5,011,930, Shionogi-Astra/Zeneca visastatin (ZD-4522) disclosed in U.S.Pat. No. 5,260,440, and related statin compounds disclosed in U.S. Pat.No. 5,753,675, pyrazole analogs of mevalonolactone derivatives asdisclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactonederivatives as disclosed in PCT application WO 86/03488,6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone as disclosed in PCT application WO 86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed inFrench Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan andthiophene derivatives as disclosed in European Patent Application No.0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat.No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No.4,499,289, keto analogs of mevinolin (lovastatin) as disclosed inEuropean Patent Application No.0,142,146 A2, and quinoline and pyridinederivatives disclosed in U.S. Pat. No. 5,506,219 and 5,691,322.

[0119] In addition, phosphinic acid compounds useful in inhibiting HMGCoA reductase suitable for use herein are disclosed in GB 2205837.

[0120] The squalene synthetase inhibitors suitable for use hereininclude, but are not limited to, α-phosphonosulfonates disclosed in U.S.Pat. No. 5,712,396, those disclosed by Biller et al, J. Med. Chem.,1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid(phosphinylmethyl)phosphonates as well as other known squalenesynthetase inhibitors, for example, as disclosed in U.S. Pat. No.4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K.,Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2,1-40 (1996).

[0121] In addition, other squalene synthetase inhibitors suitable foruse herein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293,phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987,109, 5544 and cyclopropanes reported by Capson, T. L., PhD dissertation,June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp16, 17, 40-43, 48-51, Summary.

[0122] Other hypolipidemic agents suitable for use herein include, butare not limited to, fibric acid derivatives, such as fenofibrate,gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and thelike, probucol, and related compounds as disclosed in U.S. Pat. No.3,674,836, probucol and gemfibrozil being preferred, bile acidsequestrants such as cholestyramine, colestipol and DEAE-Sephadex(Secholex®, Policexide®) and cholestagel (Sankyo/Geltex), as well aslipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolaminederivative), imanixil (HOE-402), tetrahydrolipstatin (THL),istigmastanylphosphorylcholine (SPC, Roche), aminocyclodextrin (TanabeSeiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo),Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546(disubstituted urea derivatives), nicotinic acid (niacin), acipimox,acifran, neomycin, p-aminosalicylic acid, aspirin,poly(diallylmethylamine) derivatives such as disclosed in U.S. Pat. No.4,759,923, quaternary amine poly(diallyldimethylammonium chloride) andionenes such as disclosed in U.S. Pat. No. 4,027,009, and other knownserum cholesterol lowering agents.

[0123] The hypolipidemic agent may be an ACAT inhibitor such asdisclosed in, Drugs of the Future 24, 9-15 (1999), (Avasimibe); “TheACAT inhibitor, Cl-1011 is effective in the prevention and regression ofaortic fatty streak area in hamsters”, Nicolosi et al, Atherosclerosis(Shannon, Irel). (1998), 137(1), 77-85; “The pharmacological profile ofFCE 27677: a novel ACAT inhibitor with potent hypolipidemic activitymediated by selective suppression of the hepatic secretion ofApoB100-containing lipoprotein”, Ghiselli, Giancarlo, Cardiovasc. DrugRev. (1998), 16(1), 16-30; “RP 73163: a bioavailablealkylsulfinyl-diphenylimidazole ACAT inhibitor”, Smith, C., et al,Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; “ACAT inhibitors:physiologic mechanisms for hypolipidemic and anti-atheroscleroticactivities in experimental animals”, Krause et al, Editor(s): Ruffolo,Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways(1995), 173-98, Publisher: CRC, Boca Raton, Fla.; “ACAT inhibitors:potential anti-atherosclerotic agents”, Sliskovic et al, Curr. Med.Chem. (1994), 1(3), 204-25; “Inhibitors of acyl-CoA:cholesterol O-acyltransferase (ACAT) as hypocholesterolemic agents. 6. The firstwater-soluble ACAT inhibitor with lipid-regulating activity. Inhibitorsof acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of aseries of substituted N-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureaswith enhanced hypocholesterolemic activity”, Stout et al, Chemtracts:Org. Chem. (1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co.Ltd) as well as F-1394, CS-505, F-12511, HL-004, K-10085 and YIC-C8-434.

[0124] The hypolipidemic agent may be an upregulator of LDL receptoractivity such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427(Eli Lilly).

[0125] The hypolipidemic agent may be a cholesterol absorption inhibitorpreferably Schering-Plough's SCH48461 (ezetimibe) as well as thosedisclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973(1998).

[0126] The hypolipidemic agent may be an ileal Na⁺/bile acidcotransporter inhibitor such as disclosed in Drugs of the Future, 24,425-430 (1999).

[0127] The lipid-modulating agent may be a cholesteryl ester transferprotein (CETP) inhibitor such as Pfizer's CP 529,414 as well as thosedisclosed in WO/0038722 (i.e. (torcetrapib) and in EP 818448 (Bayer) andEP 992496 and Pharmacia's SC-744 and SC-795, as well as CETi-1 andJTT-705.

[0128] The ATP citrate lyase inhibitor which may be employed in thecombination of the invention may include, for example, those disclosedin U.S. Pat. No. 5,447,954.

[0129] The other lipid agent also includes a phytoestrogen compound suchas disclosed in WO 00/30665 including isolated soy bean protein, soyprotein concentrate or soy flour as well as an isoflavone such asgenistein, daidzein, glycitein or equol, or phytosterols, phytostanol ortocotrienol as disclosed in WO 2000/015,201; a beta-lactam cholesterolabsorption inhibitor such as disclosed in EP 675714; an HDL upregulatorsuch as an LXR agonist, a PPAR alpha agonist and/or an FXR agonist; aPPAR delta agonist (e.g. GW-501516, ref: Oliver, Jr., W. R., et. al,Proc. Nat. Acad. Sci. USA, 2001, 98, 5306-5311), an LDL catabolismpromoter such as disclosed in EP 1022272; a sodium-proton exchangeinhibitor such as disclosed in DE 19622222; an LDL-receptor inducer or asteroidal glycoside such as disclosed in U.S. Pat. No. 5,698,527 and GB2304106; an anti-oxidant such as beta-carotene, ascorbic acid,α-tocopherol or retinol as disclosed in WO 94/15592 as well as Vitamin Cand an antihomocysteine agent such as folic acid, a folate, Vitamin B6,Vitamin B12 and Vitamin E; isoniazid as disclosed in WO 97/35576; acholesterol absorption inhibitor, an HMG-CoA synthase inhibitor, or alanosterol demethylase inhibitor as disclosed in WO 97/48701; a PPAR 6agonist for treating dyslipidemia; or a sterol regulating elementbinding protein-I (SREBP-1) as disclosed in WO 2000/050,574, forexample, a sphingolipid, such as ceramide, or neutral sphingomyelenase(N-SMase) or fragment thereof.

[0130] The above-mentioned U.S. patents are incorporated herein byreference. The amounts and dosages employed will be as indicated in thePhysician's Desk Reference and/or in the patents set out above.

[0131] The compounds of formula I of the invention will be employed in aweight ratio to the hypolipidemic agent (were present), within the rangefrom about 500:1 to about 1:500, preferably from about 100:1 to about1:100.

[0132] The dose administered must be carefully adjusted according toage, weight and condition of the patient, as well as the route ofadministration, dosage form and regimen and the desired result.

[0133] The dosages and formulations for the hypolipidemic agent will beas disclosed in the various patents and applications discussed above.

[0134] The dosages and formulations for the other hypolipidemic agent tobe employed, where applicable, will be as set out in the latest editionof the Physicians' Desk Reference.

[0135] For oral administration, a satisfactory result may be obtainedemploying the MTP inhibitor in an amount within the range of from about0.01 mg to about 500 mg and preferably from about 0.1 mg to about 100mg, one to four times daily.

[0136] A preferred oral dosage form, such as tablets or capsules, willcontain the MTP inhibitor in an amount of from about 1 to about 500 mg,preferably from about 2 to about 400 mg, and more preferably from about5 to about 250 mg, one to four times daily.

[0137] For oral administration, a satisfactory result may be obtainedemploying an HMG CoA reductase inhibitor, for example, pravastatin,lovastatin, simvastatin, atorvastatin, fluvastatin or rosuvastatin indosages employed as indicated in the Physician's Desk Reference, such asin an amount within the range of from about 1 to 2000 mg, and preferablyfrom about 4 to about 200 mg.

[0138] The squalene synthetase inhibitor may be employed in dosages inan amount within the range of from about 10 mg to about 2000 mg andpreferably from about 25 mg to about 200 mg.

[0139] A preferred oral dosage form, such as tablets or capsules, willcontain the HMG CoA reductase inhibitor in an amount from about 0.1 toabout 100 mg, preferably from about 0.5 to about 80 mg, and morepreferably from about 1 to about 40 mg.

[0140] A preferred oral dosage form, such as tablets or capsules willcontain the squalene synthetase inhibitor in an amount of from about 10to about 500 mg, preferably from about 25 to about 200 mg.

[0141] The hypolipidemic agent may also be a lipoxygenase inhibitorincluding a 15-lipoxygenase (15-LO) inhibitor such as benzimidazolederivatives as disclosed in WO 97/12615, 15-LO inhibitors as disclosedin WO 97/12613, isothiazolones as disclosed in WO 96/38144, and 15-LOinhibitors as disclosed by Sendobry et al “Attenuation of diet-inducedatherosclerosis in rabbits with a highly selective 15-lipoxygenaseinhibitor lacking significant antioxidant properties”, Brit. J.Pharmacology (1997) 120, 1199-1206, and Cornicelli et al,“15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target forVascular Disease”, Current Pharmaceutical Design, 1999, 5, 11-20.

[0142] The compounds of formula I and the hypolipidemic agent may beemployed together in the same oral dosage form or in separate oraldosage forms taken at the same time.

[0143] The compositions described above may be administered in thedosage forms as described above in single or divided doses of one tofour times daily. It may be advisable to start a patient on a low dosecombination and work up gradually to a high dose combination.

[0144] The preferred hypolipidemic agent is pravastatin, simvastatin,lovastatin, atorvastatin, fluvastatin or rosuvastatin as well as niacinand/or cholestagel.

[0145] The other antidiabetic agent which may be optionally employed incombination with the compound of formula I may be 1,2,3 or moreantidiabetic agents or antihyperglycemic agents including insulinsecretagogues or insulin sensitizers, or other antidiabetic agentspreferably having a mechanism of action different from the compounds offormula I of the invention, which may include biguanides, sulfonylureas, glucosidase inhibitors, PPARγ agonists such asthiazolidinediones, PPARα agonists such as fibric acid derivatives,PPARδ agonists or antagonists, PPARα/γ dual agonists, aP2 inhibitors,dipeptidyl peptidase IV (DP4) inhibitors, SGLT2 inhibitors, glycogenphosphorylase inhibitors, glucagon-like peptide-1 (GLP-1), PTP-1B(protein tyrosine phosphatase-1B) inhibitors, 11β-HSD 1(11β-hydroxy-steroid dehydrogenase 1) inhibitors and/or meglitinides, aswell as insulin.

[0146] The other antidiabetic agent may be an oral antihyperglycemicagent preferably a biguanide such as metformin or phenformin or saltsthereof, preferably metformin HCl.

[0147] Where the antidiabetic agent is a biguanide, the compounds ofstructure I will be employed in a weight ratio to biguanide within therange from about 0.001:1 to about 10:1, preferably from about 0.01:1 toabout 5:1.

[0148] The other antidiabetic agent may also preferably be a sulfonylurea such as glyburide (also known as glibenclamide), glimepiride(disclosed in U.S. Pat. No. 4,379,785), glipizide, gliclazide orchlorpropamide, other known sulfonylureas or other antihyperglycemicagents which act on the ATP-dependent channel of the β-cells, withglyburide and glipizide being preferred, which may be administered inthe same or in separate oral dosage forms.

[0149] The compounds of structure I will be employed in a weight ratioto the sulfonyl urea in the range from about 0.01:1 to about 100:1,preferably from about 0.02:1 to about 5:1.

[0150] The oral antidiabetic agent may also be a glucosidase inhibitorsuch as acarbose (disclosed in U.S. Pat. No. 4,904,769) or miglitol(disclosed in U.S. Pat. No. 4,639,436), which may be administered in thesame or in a separate oral dosage forms.

[0151] The compounds of structure I will be employed in a weight ratioto the glucosidase inhibitor within the range from about 0.01:1 to about100:1, preferably from about 0.05:1 to about 10:1.

[0152] The compounds of structure I may be employed in combination witha PPAR γ agonist such as a thiazolidinedione oral anti-diabetic agent orother insulin sensitizers (which has an insulin sensitivity effect inNIDDM patients) such as rosiglitazone (Glaxo SmithKline), pioglitazone(Takeda), Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. 5,594,016),Glaxo-Welcome's GL-262570, englitazone (CP-68722, Pfizer) ordarglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT-501(JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 orbalaglitazone (Dr. Reddy/NN), or YM-440 (Yamanouchi), preferablyrosiglitazone and pioglitazone.

[0153] The compounds of structure I will be employed in a weight ratioto the thiazolidinedione in an amount within the range from about 0.01:1to about 100:1, preferably from about 0.05 to about 10:1.

[0154] The sulfonyl urea and thiazolidinedione in amounts of less thanabout 150 mg oral antidiabetic agent may be incorporated in a singletablet with the compounds of structure I.

[0155] The compounds of structure I may also be employed in combinationwith a antihyperglycemic agent such as insulin or with glucagon-likepeptide-1 (GLP-1) such as GLP-1 (1-36) amide, GLP-1 (7-36) amide, GLP-1(7-37) (as disclosed in U.S. Pat. No. 5,614,492 to Habener, thedisclosure of which is incorporated herein by reference), as well asAC2993 (Amylin) and LY-315902 (Lilly), which may be administered viainjection, intranasal, inhalation or by transdermal or buccal devices.

[0156] Where present, metformin, the sulfonyl ureas, such as glyburide,glimepiride, glipyride, glipizide, chlorpropamide and gliclazide and theglucosidase inhibitors acarbose or miglitol or insulin (injectable,pulmonary, buccal, or oral) may be employed in formulations as describedabove and in amounts and dosing as indicated in the Physician's DeskReference (PDR).

[0157] Where present, metformin or salt thereof may be employed inamounts within the range from about 500 to about 2000 mg per day whichmay be administered in single or divided doses one to four times daily.

[0158] Where present, the thiazolidinedione anti-diabetic agent may beemployed in amounts within the range from about 0.01 to about 2000mg/day which may be administered in single or divided doses one to fourtimes per day.

[0159] Where present insulin may be employed in formulations, amountsand dosing as indicated by the Physician's Desk Reference.

[0160] Where present GLP-1 peptides may be administered in oral buccalformulations, by nasal administration or parenterally as described inU.S. Pat. Nos. 5,346,701 (TheraTech), 5,614,492 and 5,631,224 which areincorporated herein by reference.

[0161] The other antidiabetic agent may also be a PPAR α/γ dual agonistsuch as AZ-242/tesaglitazar (Astra/Zeneca; as described: in B. Ljung et.al., J. Lipid Res., 2002, 43, 1855-1863), GW-409544 (Glaxo-Wellcome),KRP-297/MK-767 (Kyorin/Merck; as described in: K. Yajima et. al., Am. J.Physiol. Endocrinol. Metab., 2003, 284: E966-E971) as well as thosedisclosed by Murakami et al, “A Novel Insulin Sensitizer Acts As aColigand for Peroxisome Proliferation—Activated Receptor Alpha (PPARalpha) and PPAR gamma. Effect on PPAR alpha Activation on Abnormal LipidMetabolism in Liver of Zucker Fatty Rats”, Diabetes 47, 1841-1847 (1998)or the compounds (from Bristol-Myers Squibb) described in U.S. Pat. No.6,414,002.

[0162] The antidiabetic agent may be an SGLT2 inhibitor such asdisclosed in U.S. provisional application No. 60/158,773, filed Oct. 12,1999 (attorney file LA49), employing dosages as set out therein.Preferred are the compounds designated as preferred in the aboveapplication.

[0163] The antidiabetic agent may be an aP2 inhibitor such as disclosedin U.S. application Ser. No. 09/391,053, filed Sep. 7, 1999, and in U.S.provisional application No. 60/127,745, filed Apr. 5, 1999 (attorneyfile LA27*), employing dosages as set out herein. Preferred are thecompounds designated as preferred in the above application.

[0164] The antidiabetic agent may be a DP4 (Dipeptidyl peptidase IV)inhibitor such as disclosed in Provisional Application No. 60/188,555filed Mar. 10, 2000 (attorney file LA50), WO99/38501, WO99/46272,WO99/67279 (PROBIODRUG), WO99/67278 (PROBIODRUG), WO99/61431(PROBIODRUG), NVP-DPP728A(1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine)(Novartis) (preferred) as disclosed by Hughes et al, Biochemistry,38(36), 11597-11603, 1999, TSL-225(tryptophyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (disclosedby Yamada et al, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540,2-cyanopyrrolidides and 4-cyanopyrrolidides as disclosed by Ashworth etal, Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and2745-2748 (1996) employing dosages as set out in the above references.

[0165] The meglitinide which may optionally be employed in combinationwith the compound of formula I of the invention may be repaglinide,nateglinide (Novartis) or KAD1229 (PF/Kissei), with repaglinide beingpreferred.

[0166] The compound of formula I will be employed in a weight ratio tothe meglitinide, PPAR γ agonist, PPAR α/γ dual agonist, aP2 inhibitor,DP4 inhibitor or SGLT2 inhibitor within the range from about 0.01:1 toabout 100:1, preferably from about 0.05 to about 10:1.

[0167] The other type of therapeutic agent which may be optionallyemployed with a compound of formula I may be 1, 2, 3 or more of ananti-obesity agent including a melanocortin receptor (MC4R) agonist, amelanin-concentrating hormone receptor (MCHR) antagonist, a growthhormone secretagogue receptor (GHSR) antagonist, an orexin receptorantagonist, a CCK (cholecystokinin) agonist, a GLP-1 agonists, NPY1 orNPY5 antagonist, a corticotropin releasing factor (CRF) antagonist, ahistamine receptor-3 (H3) modulator, a PPARγ modulator, a PPARδmodulator, a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin(and dopamine) reuptake inhibitor, a erotonin receptor agonist (e.g.BVT-933), an aP2 inhibitor, a thyroid receptor agonist and/or ananorectic agent.

[0168] The beta 3 adrenergic agonist which may be optionally employed incombination with a compound of formula I may be AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other knownbeta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615,5,491,134, 5,776,983 and 5,488,064, with AJ9677, L750,355 and CP331648being preferred.

[0169] The lipase inhibitor which may be optionally employed incombination with a compound of formula I may be orlistat or ATL-962(Alizyme), with orlistat being preferred.

[0170] The serotonin (and dopoamine) reuptake inhibitor which may beoptionally employed in combination with a compound of formula I may besibutramine, topiramate (Johnson & Johnson) or CNTF/axokine (Regeneron),with sibutramine and topiramate being preferred.

[0171] The thyroid receptor agonist which may be optionally employed incombination with a compound of formula I may be a thyroid receptorligand as disclosed in WO97/21993 (U. Cal SF), WO99/00353 (KaroBio),GB98/284425 (KaroBio), and U.S. Provisional Application No. 60/183,223filed Feb. 17, 2000, with compounds of the KaroBio applications and theabove U.S. provisional application being preferred.

[0172] The anorectic agent which may be optionally employed incombination with a compound of formula I may be fenfluramine,dexfenfluramine, fluxoxamine, fluoxetine, paroxetine, sertraline,chlorphentermine, clorofex, clortermine, picilorex, sibutramine,dexamphetamine, phentermine, phenylpropanolamine or mazindol. Otheranorectic agents which may be optionally employed in combination with acompound of formula I include CNTF (ciliary neurotrophic factor)/Axokine(Regeneron), BDNF (brain-derived neurotrophic factor), leptin orcannabinoid receptor antagonists, such as SR-141716/rimonabant (Sanofi)or SLV-319 (Solvay).

[0173] The various anti-obesity agents described above may be employedin the same dosage form with the compound of formula I or in differentdosage forms, in dosages and regimens as generally known in the art orin the PDR.

[0174] The antihypertensive agents which may be employed in combinationwith the compound of formula I of the invention include ACE inhibitors,angiotensin II receptor antagonists, NEP/ACE inhibitors, as well ascalcium channel blockers, β-adrenergic blockers and other types ofantihypertensive agents including diuretics.

[0175] The angiotensin converting enzyme inhibitor which may be employedherein includes those containing a mercapto (—S—) moiety such assubstituted proline derivatives, such as any of those disclosed in U.S.Pat. No. 4,046,889 to Ondetti et al mentioned above, with captopril,that is, 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline, beingpreferred, and mercaptoacyl derivatives of substituted prolines such asany of those disclosed in U.S. Pat. No. 4,316,906 with zofenopril beingpreferred.

[0176] Other examples of mercapto containing ACE inhibitors that may beemployed herein include rentiapril (fentiapril, Santen) disclosed inClin. Exp. Pharmacol. Physiol. 10:131 (1983); as well as pivopril andYS980.

[0177] Other examples of angiotensin converting enzyme inhibitors whichmay be employed herein include any of those disclosed in U.S. Pat. No.4,374,829 mentioned above, withN-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline, that is,enalapril, being preferred, any of the phosphonate substituted amino orimino acids or salts disclosed in U.S. Pat. No. 4,452,790 with(S)-1-[6-amino-2-[[hydroxy-(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-prolineor (ceronapril) being preferred, phosphinylalkanoyl prolines disclosedin U.S. Pat. No. 4,168,267 mentioned above with fosinopril beingpreferred, any of the phosphinylalkanoyl substituted prolines disclosedin U.S. Pat. No. 4,337,201, and the phosphonamidates disclosed in U.S.Pat. No. 4,432,971 discussed above.

[0178] Other examples of ACE inhibitors that may be employed hereininclude Beecham's BRL 36,378 as disclosed in European Patent ApplicationNos. 80822 and 60668; Chugai's MC-838 disclosed in C.A. 102:72588v andJap. J. Pharmacol. 40:373 (1986); Ciba-Geigy's CGS 14824(3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1-(3S)-benzazepine-1acetic acid HCl) disclosed in U.K. Patent No. 2103614 and CGS 16,617(3(S)-[[(1S)-5-amino-1-carboxypentyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-ethanoicacid) disclosed in U.S. Pat. No. 4,473,575; cetapril (alacepril,Dainippon) disclosed in Eur. Therap. Res. 39:671 (1986); 40:543 (1986);ramipril (Hoechsst) disclosed in Euro. Patent No. 79-022 and Curr. Ther.Res. 40:74 (1986); Ru 44570 (Hoechst) disclosed in Arzneimittelforschung34:1254 (1985), cilazapril (Hoffman-LaRoche) disclosed in J. Cardiovasc.Pharmacol. 9:39 (1987); R 31-2201 (Hoffman-LaRoche) disclosed in FEBSLett. 165:201 (1984); lisinopril (Merck), indalapril (delapril)disclosed in U.S. Pat. No. 4,385,051; indolapril (Schering) disclosed inJ. Cardiovasc. Pharmacol. 5:643, 655 (1983), spirapril (Schering)disclosed in Acta. Pharmacol. Toxicol. 59 (Supp. 5):173 (1986);perindopril (Servier) disclosed in Eur. J. clin. Pharmacol. 31:519(1987); quinapril (Warner-Lambert) disclosed in U.S. Pat. No. 4,344,949and CI925 (Warner-Lambert)([3S-[2[R(*)R(*)]]3R(*)]-2-[2-[[1-(ethoxy-carbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid HCl)disclosed in Pharmacologist 26:243, 266 (1984), WY-44221(Wyeth) disclosed in J. Med. Chem. 26:394 (1983).

[0179] Preferred ACE inhibitors are captopril, fosinopril, enalapril,lisinopril, quinapril, benazepril, fentiapril, ramipril and moexipril.

[0180] NEP/ACE inhibitors may also be employed herein in that theypossess neutral endopeptidase (NEP) inhibitory activity and angiotensinconverting enzyme (ACE) inhibitory activity. Examples of NEP/ACEinhibitors suitable for use herein include those disclosed in U.S. Pat.Nos. 5,362,727, 5,366,973, 5,225,401, 4,722,810, 5,223,516, 4,749,688,U.S. Pat. No. 5,552,397, U.S. Pat. No. 5,504,080, U.S. Pat. No.5,612,359,U.S. Pat. No. 5,525,723, European Patent Application 0599,444,0481,522, 0599,444, 0595,610, European Patent Application 0534363A2,534,396 and 534,492, and European Patent Application 0629627A2.

[0181] Preferred are those NEP/ACE inhibitors and dosages thereof whichare designated as preferred in the above patents/applications which U.S.patents are incorporated herein by reference; most preferred areomapatrilat, BMS 189,921([S-(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid (gemopatrilat)) and CGS 30440.

[0182] The angiotensin II receptor antagonist (also referred to hereinas angiotensin II antagonist or AII antagonist) suitable for use hereinincludes, but is not limited to, irbesartan, losartan, valsartan,candesartan, telmisartan, tasosartan or eprosartan, with irbesartan,losartan or valsartan being preferred.

[0183] A preferred oral dosage form, such as tablets or capsules, willcontain the ACE inhibitor or AII antagonist in an amount within therange from abut 0.1 to about 500 mg, preferably from about 5 to about200 mg and more preferably from about 10 to about 150 mg.

[0184] For parenteral administration, the ACE inhibitor, angiotensin IIantagonist or NEP/ACE inhibitor will be employed in an amount within therange from about 0.005 mg/kg to about 10 mg/kg and preferably from about0.01 mg/kg to about 1 mg/kg.

[0185] Where a drug is to be administered intravenously, it will beformulated in conventional vehicles, such as distilled water, saline,Ringer's solution or other conventional carriers.

[0186] It will be appreciated that preferred dosages of ACE inhibitorand AII antagonist as well as other antihypertensives disclosed hereinwill be as set out in the latest edition of the Physician's DeskReference (PDR).

[0187] Other examples of preferred antihypertensive agents suitable foruse herein include omapatrilat (Vanlev®) amlodipine besylate (Norvasc®),prazosin HCl (Minipress®), verapamil, nifedipine, nadolol, diltiazem,felodipine, nisoldipine, isradipine, nicardipine, atenolol, carvedilol,sotalol, terazosin, doxazosin, propranolol, and clonidine HCl(Catapres®).

[0188] Diuretics which may be employed in combination with compounds offormula I include hydrochlorothiazide, torasemide, furosemide,spironolactono, and indapamide.

[0189] Antiplatelet agents which may be employed in combination withcompounds of formula I of the invention include aspirin, clopidogrel,ticlopidine, dipyridamole, abciximab, tirofiban, eptifibatide,anagrelide, and ifetroban, with clopidogrel and aspirin being preferred.

[0190] The antiplatelet drugs may be employed in amounts as indicated inthe PDR. Ifetroban may be employed in amounts as set out in U.S. Pat.No. 5,100,889.

[0191] Antiosteoporosis agents suitable for use herein in combinationwith the compounds of formula I of the invention include parathyroidhormone or bisphosphonates, such as MK-217 (alendronate) (Fosamax®).Dosages employed will be as set out in the PDR.

[0192] In carrying our the method of the invention, a pharmaceuticalcomposition will be employed containing the compounds of structure I,with or without another therapeutic agent, in association with apharmaceutical vehicle or diluent. The pharmaceutical composition can beformulated employing conventional solid or liquid vehicles or diluentsand pharmaceutical additives of a type appropriate to the mode ofdesired administration. The compounds can be administered to mammalianspecies including humans, monkeys, dogs, etc. by an oral route, forexample, in the form of tablets, capsules, granules or powders, or theycan be administered by a parenteral route in the form of injectablepreparations. The dose for adults is preferably between 50 and 2,000 mgper day, which can be administered in a single dose or in the form ofindividual doses from 1-4 times per day.

[0193] A typical capsule for oral administration contains compounds ofstructure I (250 mg), lactose (75 mg) and magnesium stearate (15 mg).The mixture is passed through a 60 mesh sieve and packed into a No. 1gelatin capsule.

[0194] A typical injectable preparation is produced by asepticallyplacing 250 mg of compounds of structure I into a vial, asepticallyfreeze-drying and sealing. For use, the contents of the vial are mixedwith 2 mL of physiological saline, to produce an injectable preparation.

[0195] The following abbreviations are employed in the Examples:

[0196] Ph=phenyl

[0197] Bn=benzyl

[0198] t-Bu=tertiary butyl

[0199] Me=methyl

[0200] Et=ethyl

[0201] TMS=trimethylsilyl

[0202] TMSN₃=trimethylsilyl azide

[0203] TMSCHN₂=trimethylsilyl diazomethane

[0204] TBS=tert-butyldimethylsilyl

[0205] TBDPS=tert-butyldiphenylsilyl

[0206] FMOC=fluorenylmethoxycarbonyl

[0207] Boc=tert-butoxycarbonyl

[0208] Cbz=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl

[0209] THF=tetrahydrofuran

[0210] Et₂O=diethyl ether

[0211] hex=hexanes

[0212] EtOAc=ethyl acetate

[0213] DMF=dimethyl formamide

[0214] MeOH=methanol

[0215] EtOH=ethanol

[0216] i-PrOH=IPA=isopropanol

[0217] DMSO=dimethyl sulfoxide

[0218] DME=1,2 dimethoxyethane

[0219] DCE=1,2 dichloroethane

[0220] HMPA=hexamethyl phosphoric triamide

[0221] HOAc or AcOH=acetic acid

[0222] TFA=trifluoroacetic acid

[0223] PTSA=pTSOH=para-toluenesulfonic acid

[0224] i-Pr₂NEt=diisopropylethylamine

[0225] Et₃N=TEA=triethylamine

[0226] Et₂NH=diethylamine

[0227] NMM=N-methyl morpholine

[0228] DMAP=4-dimethylaminopyridine

[0229] NaBH₄=sodium borohydride

[0230] NaBH(OAc)₃=sodium triacetoxyborohydride

[0231] DIBALH=diisobutyl aluminum hydride

[0232] LiAlH₄=lithium aluminum hydride

[0233] n-BuLi=n-butyllithium

[0234] Pd/C=palladium on carbon

[0235] PtO₂=platinum oxide

[0236] KOH=potassium hydroxide

[0237] NaOH=sodium hydroxide

[0238] LiOH=lithium hydroxide

[0239] K₂CO₃=potassium carbonate

[0240] NaHCO₃=sodium bicarbonate

[0241] H₂SO₄=sulfuric acid

[0242] KHSO₄=potassium hydrogen phosphate

[0243] DBU=1,8-diazabicyclo[5.4.0]undec-7-ene

[0244] EDC (or EDC.HCl) or EDCI (or EDCI.HCl) orEDAC=3-ethyl-3′-(dimethylamino)propyl-carbodiimide hydrochloride (or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)

[0245] HOBT or HOBT.H₂O=1-hydroxybenzotriazole hydrate

[0246] HOAT=1-Hydroxy-7-azabenzotriazole

[0247] BOP reagent=benzotriazol-1-yloxy-tris (dimethylamino) phosphoniumhexafluorophosphate

[0248] NaN(TMS)₂=sodium hexamethyldisilazide or sodiumbis(trimethylsilyl)amide

[0249] Ph₃P=triphenylphosphine

[0250] Pd(OAc)₂=Palladium acetate

[0251] (Ph₃P)₄Pd^(o)=tetrakis triphenylphosphine palladium

[0252] DEAD=diethyl azodicarboxylate

[0253] DIAD=diisopropyl azodicarboxylate

[0254] Cbz-Cl=benzyl chloroformate

[0255] CAN=ceric ammonium nitrate

[0256] SiO₂=silica gel

[0257] SAX=Strong Anion Exchanger

[0258] SCX=Strong Cation Exchanger

[0259] Ar=argon

[0260] N₂ nitrogen

[0261] min=minute(s)

[0262] h or hr=hour(s)

[0263] L=liter

[0264] mL=milliliter

[0265] μL=microliter

[0266] μM=micromolar

[0267] g=gram(s)

[0268] mg=milligram(s)

[0269] mol=moles

[0270] mmol=millimole(s)

[0271] meq=milliequivalent

[0272] RT=room temperature

[0273] sat or sat'd=saturated

[0274] aq.=aqueous

[0275] TLC=thin layer chromatography

[0276] HPLC=high performance liquid chromatography

[0277] LC/MS=high performance liquid chromatography/mass

[0278] spectrometry

[0279] MS or Mass Spec=mass spectrometry

[0280] NMR=nuclear magnetic resonance

[0281] NMR spectral data: s=singlet; d=doublet; m=

[0282] multiplet; br=broad; t=triplet

[0283] mp=melting point

[0284] ee=enantiomeric excess

[0285] The following examples represent preferred embodiments of theinvention.

EXAMPLE 1

[0286]

[0287] To a 0° C. solution of 4-methyl-2-phenyl-1,2,3triazole-5-carboxylic acid (2.0 g; 9.8 mmol) in anhydrous THF (30 mL)was added borane in THF (29.5 mL of a 1 M solution; 29.5 mmol) dropwise.The reaction was allowed to warm to RT and the clear solution wasstirred at RT for 20 h, then poured into an ice/H₂O mixture. The mixturewas extracted with EtOAc (100 mL). The organic phase was washed with H₂O(50 mL), 1 N aqueous NaOH (50 mL), H₂O (2×50 mL), dried (Na₂SO₄), andconcentrated in vacuo to give Part A compound (1.80 g; 100%) as whitecrystals.

[0288] To a 0° C. solution of Part A compound (300 mg; 1.71 mmol),4-hydroxybenzaldehyde (232 mg; 1.90 mmol) and Ph₃P (524 mg; 2.0 mmol) inanhydrous THF (15 mL) was added DEAD (400 μL; 2.2 mmol) dropwise and theresulting solution was allowed to warm to RT and stirred overnight atRT. Volatiles were removed in vacuo and the residue was chromatographed(SiO₂; stepwise gradient from 3:1 to 1:1 hexane:EtOAc) to provide Part Bcompound (440 mg; 88%) as a solid.

[0289] A mixture of Part B compound (100 mg; 0.34 mmol), glycine methylester hydrochloride (50 mg; 0.40 mmol) and Et₃N (50 mg; 0.50 mmol) inMeOH (2 mL) was stirred at RT for 5 h. The reaction mixture was cooledto 0° C. and NaBH₄ (18 mg; 0.50 mmol) was added portionwise (exothermicreaction). The reaction was allowed to warm to RT and stirred at RT for30 min, then partitioned between EtOAc and H2O. The organic phase wasdried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 3:1 to 1:1 hexane:EtOAc)to give Part C compound (72 mg; 66%) as an oil.

[0290] A solution of Part C compound (10 mg; 0.032 mmol),4-methoxyphenyl chloroformate (6 mg; 0.032 mmol) and Et₃N (200 μL; 1.44mmol) in CH₂Cl₂ (1 mL) was stirred at RT for 30 min. The reaction wascomplete by TLC at this point. Volatiles were removed in vacuo and theresidue was dissolved in THF (2 mL) and aqueous LiOH (0.5 mL of a 1 Msolution) was added. The reaction was stirred at RT overnight, afterwhich volatiles were removed in vacuo. The residue was partitionedbetween EtOAc and excess aqueous 1M HCl. The organic phase was washedwith H₂O, dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified by preparative HPLC (from 70% A:30% B to 0% A:100% B(A=90%H₂O/10% MeOH+0.1% TFA);(B=90% MeOH/10% H₂O+0.1% TFA) for 10 min at 25ml/min; detection at 220 nm.; YMC ODS 20×100 mm column) to give thetitle compound (7 mg; 43%) as a solid.

[0291] [M+H]⁺=503.2

[0292]¹H NMR (CHCl₃): δ 2.44 (3H, s), 3.79 (3H, s), 4.04-4.56 (2H, 2s),4.58-4.68 (2H, 2s), 5.19-5.21 (2H, 2s), 6.85-6.92 (2H, m), 7.00-7.75(4H, m), 7.25-7.38 (3H, m), 7.44-7.48 (2H, m), 8.00-8.02 (2H, m)

EXAMPLE 2

[0293]

[0294] A solution of Example 1 Part C compound (10 mg; 0.032 mmol),benzoyl chloride (5 mg; 0.032 mmol) and Et₃N (200 μL; 1.44 mmol) inCH₂Cl₂ (1 mL) was stirred at RT for 30 min. The reaction was complete byTLC at this point. Volatiles were removed in vacuo and the residue wasdissolved in THF (2 mL) and aqueous LiOH (0.5 mL of a 1 M solution) wasadded. The reaction was stirred at RT overnight, after which volatileswere removed in vacuo. The residue was partitioned between EtOAc andexcess aqueous 1M HCl. The organic phase was washed with H₂O, dried(Na₂SO₄) and concentrated in vacuo. The residue was purified bypreparative HPLC (from 70% A: 30% B to 0% A:100% B(A=90% H₂O/10%MeOH+0.1% TFA);(B=90% MeOH/10% H₂O+0.1% TFA) for 10 min at 25 ml/min;detection at 220 nm.; YMC ODS 20×100 mm column) to give the titlecompound (9 mg; 60%) as a solid.

EXAMPLE 3

[0295]

[0296] To a 0° C. solution of Example 1 Part A compound (300 mg; 1.71mmol), 3-hydroxybenzaldehyde (232 mg; 1.90 mmol) and Ph₃P (524 mg; 2.0mmol) in THF (15 mL) was added DEAD (400 μL; 2.2 mmol) dropwise and theresulting solution was allowed to warm to RT and stirred overnight atRT. Volatiles were removed in vacuo and the residue was chromatographed(SiO₂; stepwise gradient from 3:1 to 1:1 hexane:EtOAc) to provide Part Bcompound (390 mg; 77%) as a solid.

[0297] A mixture of Part A compound (100 mg; 0.34 mmol), glycine methylester hydrochloride (50 mg; 0.40 mmol) and Et₃N (50 mg; 0.50 mmol) inMeOH (2 mL) was stirred at RT for 5 h. The reaction mixture was cooledto 0° C. and NaBH₄ (18 mg; 0.50 mmol) was added portionwise (exothermicreaction). The reaction was allowed to warm to RT and stirred at RT for30 min, then partitioned between EtOAc and H₂O. The organic phase wasdried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 3:1 to 1:1 hexane:EtOAc)to give Part C compound (46 mg; 42%) as an oil.

[0298] A solution of Part B compound (10 mg; 0.032 mmol),4-methoxyphenyl chloroformate (6 mg; 0.032 mmol) and Et₃N (200 μL; 1.44mmol) in CH₂Cl₂ (1 mL) was stirred at RT for 30 min. The reaction wascomplete by TLC at this point. Volatiles were removed in vacuo and theresidue was dissolved in THF (2 mL) and aqueous LiOH (0.5 mL of a 1 Msolution) was added. The reaction was stirred at RT overnight, afterwhich volatiles were removed in vacuo. The residue was partitionedbetween EtOAc and excess aqueous 1M HCl. The organic phase was washedwith H₂O, dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified by preparative HPLC (from 70% A: 30% B to 0% A:100% B(A=90%H₂O/10% MeOH+0.1% TFA);(B=90% MeOH/10% H₂O+0.1% TFA) for 10 min at 25ml/min; detection at 220 nm.; YMC ODS 20×100 mm column) to give thetitle compound (4 mg; 26%) as a solid.

[0299] [M+H]⁺=503.2

[0300]¹H NMR (CDCl₃): δ 2.44 (3H, s), 3.78 (3H, s), 4.07? (2H, ),4.63-4.72 (2H,), 5.20-5.22 (2H,), 6.85-7.05 (7H, m), 7.26-7.32 (2H, m),7.43-7.47 (2H, m), 7.99-8.01 (2H, m)

[0301] EXAMPLE 4

[0302] A solution of Example 3 Part B compound (10 mg; 0.032 mmol),benzoyl chloride (5 mg; 0.032 mmol) and Et₃N (200 μL; 1.44 mmol) inCH₂Cl₂ (1 mL) was stirred at RT for 30 min. The reaction was complete byTLC at this point. Volatiles were removed in vacuo and the residue wasdissolved in THF (2 mL) and aqueous LiOH (0.5 mL of a 1 M solution) wasadded. The reaction was stirred at RT overnight, after which volatileswere removed in vacuo. The residue was partitioned between EtOAc andexcess aqueous 1M HCl. The organic phase was washed with H₂O, dried(Na₂SO₄) and concentrated in vacuo. The residue was purified bypreparative HPLC (from 70% A:30% B to 0% A:100% B(A=90% H₂O/10%MeOH+0.1% TFA);(B=90% MeOH/10% H2O+0.1% TFA) for 10 min at 25 ml/min;detection at 220 nm.; YMC ODS 20×100 mm column) to give the titlecompound (16 mg; 90%) as a solid.

EXAMPLE 5

[0303]

[0304] To a solution of Example 1 Part A compound (500 mg; 2.86 mmol) inCH₂Cl₂ (10 mL) was added PBr₃ (1.55 g; 2.86 mmol) and the solution wasstirred at RT for 2 h. The reaction was partitioned between EtOAc (20mL) and saturated aqueous NaHCO₃ (20 mL). The organic phase was washedsuccessively with aqueous NaHCO₃ and water, dried (Na₂SO₄) andconcentrated in vacuo to give Part A compound (600 mg; 83%) as a whitesolid.

[0305] A mixture of Part A compound (600 mg; 2.38 mmol), KCN (300 mg;2.50 mmol) and 18-crown-6 (200 mg; 0.76 mmol) in MeCN (10 mL) wasrefluxed under an atmosphere of N₂ for 2 h. HPLC indicated that allstarting bromide had been consumed at this point. The reaction mixturewas partitioned between EtOAc and H₂O. The organic phase was dried(Na₂SO₄) and concentrated in vacuo to give Part B compound (500 mg; 99%)as an oil, which was used in the next step without further purification.

[0306] A solution of Part B compound (2.0 g; 10.0 mmol) in concentratedHCl (2.2 mL) and MeOH (35 mL) was heated in a sealed tube for 3 h at 85°C. Analytical HPLC showed that the mixture contained 80% product, 10%acid and 10% starting material. The reaction was cooled to RT andpartitioned between EtOAc and saturated aqueous NaHCO₃. The organicphase was washed with water, dried (Na₂SO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; stepwise gradient from 10:1 to5:1 hexane:EtOAc) to give Part C compound (1.30 g; 56%) as a whitesolid.

[0307] To a −78° C. solution of Part C compound (1.30 g; 5.62 mmol) inTHF (5 mL) was added dropwise a solution of LiAlH₄ in THF (5.0 mL of a 1M solution). The reaction mixture was allowed to warm to RT and stirredat RT for 2 h. At this point HPLC showed that all starting material hadbeen consumed. The reaction was quenched by cautious dropwise additionof H₂O at 0° C. The resulting white solid was filtered off and thefiltrate was concentrated in vacuo. The residue was chromatographed(SiO₂; stepwise gradient from 2:1 to 1:1 hexane:EtOAc) to give Part Dcompound (1.0 g; 88%) as a white solid.

[0308] To a 0° C. solution of Part D compound (100 mg; 0.49 mmol),4-hydroxybenzaldehyde (61 mg; 0.50 mmol) and Ph₃P (140 mg; 0.53 mmol) inanhydrous THF (2 mL) was added DEAD (95 μL; 0.60 mmol) dropwise and theresulting solution was allowed to warm to RT and stirred overnight atRT. Volatiles were removed in vacuo and the residue was chromatographed(SiO₂; stepwise gradient from 5:1 to 3:1 hexane:EtOAc) to provide Part Ecompound (163 mg; 99%) as a solid.

[0309] A mixture of Part E compound (100 mg; 0.33 mmol), glycine methylester hydrochloride (50 mg; 0.40 mmol) and Et₃N (70 μL; 0.50 mmol) inMeOH (2 mL) was stirred at RT for 5 h. The reaction mixture was cooledto 0° C. and NaBH₄ (15 mg; 0.40 mmol) was added portionwise (exothermicreaction). The reaction was allowed to warm to RT and stirred at RT for30 min, then partitioned between EtOAc and H₂O. The organic phase wasdried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 3:1 to 1:1 hexane:EtOAc)to give Part F compound (100 mg; 80%) as an oil.

[0310] A solution of Part F compound (100 mg; 0.26 mmol),4-methoxyphenyl chloroformate (56 mg; 0.30 mmol) and Et₃N (42 μL; 0.30mmol) in CH₂Cl₂ (1 mL) was stirred at RT for 30 min. The reaction wascomplete by TLC at this point. Volatiles were removed in vacuo and theresidue was dissolved in THF (3 mL) and aqueous LiOH (1.0 mL of a 1 Msolution) was added. The reaction was stirred at RT overnight, afterwhich volatiles were removed in vacuo. The residue was partitionedbetween EtOAc and excess aqueous 1M HCl. The organic phase was washedwith H₂O, dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified by preparative HPLC (from 70% A:30% B to 0% A:100% B(A=90%H₂O/10% MeOH+0.1% TFA);(B=90% MeOH/10% H₂O+0.1% TFA) for 30 min at 25ml/min; detection at 220 nm.; YMC ODS 30×250 mm column) to give thetitle compound (54 mg; 40%) as a solid.

[0311] [M+H]⁺=517.3

[0312]¹H NMR (CDCl₃): δ 2.40 (3H, s), 3.17-3.20 (2H, m), 3.78 (3H, s),4.02-4.03 (2H, m), 4.26-4.30 (2H, m), 4.55-4.60 (2H, ss), 6.81-6.92 (5H,m), 6.99-7.10 (2H, m), 7.20-7.31 (2H, m), 7.41-7.46 (2H, m), 7.96-7.98(2H, m).

EXAMPLE 6

[0313]

[0314] To a 0° C. solution of Example 5 Part D compound (100 mg; 0.49mmol), 3-hydroxybenzaldehyde (61 mg; 0.50 mmol) and Ph₃P (140 mg; 0.53mmol) in anhydrous THF (2 mL) was added DEAD (95 μL; 0.60 mmol) dropwiseand the resulting solution was allowed to warm to RT and stirredovernight at RT. Volatiles were removed in vacuo and the residue waschromatographed (SiO₂; stepwise gradient from 5:1 to 3:1 hexane:EtOAc)to provide Part A compound (45 mg; 30%) as a solid.

[0315] A mixture of Part A compound (50 mg; 0.33 mmol), glycine methylester hydrochloride (50 mg; 0.40 mmol) and Et₃N (70 μL; 0.50 mmol) inMeOH (2 mL) was stirred at RT for 5 h. The reaction mixture was cooledto 0° C. and NaBH₄ (15 mg; 0.40 mmol) was added portionwise (exothermicreaction). The reaction was allowed to warm to RT and stirred at RT for30 min, then partitioned between EtOAc and H₂O. The organic phase wasdried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 3:1 to 1:1 hexane:EtOAc)to give Part F compound (100 mg; 81%) as an oil.

[0316] A solution of Part B compound (100 mg; 0.26 mmol),4-methoxyphenyl chloroformate (56 mg; 0.30 mmol) and Et₃N (42 μL; 0.30mmol) in CH₂Cl₂ (1 mL) was stirred at RT for 30 min. The reaction wascomplete by TLC at this point. Volatiles were removed in vacuo and theresidue was dissolved in THF (3 mL) and aqueous LiOH (1.0 mL of a 1 Msolution) was added. The reaction was stirred at RT overnight, afterwhich volatiles were removed in vacuo. The residue was partitionedbetween EtOAc and excess aqueous 1M HCl. The organic phase was washedwith H₂O, dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified by preparative HPLC (from 70% A:30% B to 0% A:100% B(A=90%H₂O/10% MeOH+0.1% TFA);(B=90% MeOH/10% H₂O+0.1% TFA) for 30 min at 25ml/min; detection at 220 nm.; YMC ODS 30×250 mm column) to give thetitle compound (26 mg; 19%) as a solid.

[0317] [M+H]⁺=517.3

[0318]¹H NMR (CDCl₃): δ 2.41 (3H, s), 3.18-3.20 (2H, m), 3.77 (3H, s),4.06 (2H,d, J=4.4 Hz), 4.28-4.32 (2H, m), 4.60-4.70 (2H, ss), 6.80-6.91(5H, m), 7.01-7.05 (2H, m), 7.25-7.31 (2H, m), 7.41-7.45 (2H, m),7.95-7.97 (2H, m)

EXAMPLE 7

[0319]

[0320] A solution of Example 5 Part D compound (900 mg; 4.43 mmol) inPBr₃ (5.0 mL of a 1 M solution in CH₂Cl₂) was stirred at RT for 30 min.At this point HPLC showed that all starting material had been consumed.Volatiles were removed in vacuo and the residue was partitioned betweenEtOAc and H₂O. The organic phase was washed with saturated aqueousNaHCO₃ and concentrated in vacuo. The residue was chromatographed (SiO₂;hexane:EtOAc) to give the crude bromide (427 mg; 36%). A mixture of thismaterial, KCN (290 mg; 4.43 mmol) and 18-crown-6 (1.2 g; 4.54 mmol) inMeCN (5 mL) was refluxed under an atmosphere of N₂ for 2 h. The reactionmixture was partitioned between EtOAc and H₂O. The organic phase wasdried (Na₂SO₄) and concentrated in vacuo to give Part A compound (300mg; 88%) as an oil, which was used in the next step without furtherpurification.

[0321] A solution of Part A compound (300 mg; 1.41 mmol) in concentratedHCl (2 mL) and MeOH (5 mL) was heated at 85° C. in a sealed tube for 3h. The reaction was cooled to RT, then partitioned between EtOAc (20 mL)and excess aqueous 1 M NaOH and aqueous 1 M NaHCO₃. The organic extractwas washed with H₂O, dried (Na₂SO₄) and concentrated in vacuo. Theresidue was treated with trimethylsilyldiazomethane (1 mL of a 2.0 Msolution in hexanes; 2.0 mmol) and MeOH (3 mL) for 1 h at RT, afterwhich volatiles were removed in vacuo. The residue was chromatographed(SiO₂; 4:1 hexane:EtOAc) to give Part B compound (260 mg; 99%) as acolorless oil.

[0322] To a 0° C. solution of Part B compound (260 mg; 1.06 mmol) in THF(10 mL) was added dropwise a solution of LiAlH₄ in THF (1.0 mL of a 1 Msolution; 1.0 mmol). The reaction mixture was allowed to warm to RT andstirred at RT for 1 h. At this point TLC showed that reaction wascomplete. The reaction was quenched at 0° C. by dropwise addition of H₂O(0.5 mL). The solids were filtered off and the filtrate was concentratedin vacuo to give the crude alcohol as an oil. To a 0° C. solution ofthis material and Et₃N (101 mg; 1.0 mmol) in CH₂Cl₂(2 mL) was addedmethanesulfonyl chloride (121 mg; 1.0 mmol) dropwise. The reactionmixture was allowed to warm to RT and stirred at RT for 2 h, at whichpoint TLC indicated that all starting material had been consumed. Themixture was partitioned between EtOAc and H₂O, and the organic phase wasdried (Na₂SO₄) and concentrated in vacuo to give Part C compound (325mg; 99%) as an oil. This crude material was used in the next stepwithout further purification.

[0323] A mixture of Part C compound (150 mg; 0.51 mmol),4-hydroxybenzaldehyde (62 mg; 0.51 mmol) and K₂CO₃ (210 mg; 1.53 mmol)in DMF (1 mL) was heated at 100° C. in an oil bath for 2 h. At thispoint HPLC indicated that all starting material had been consumed. Thereaction was cooled to RT and poured into ice-water (20 mL) and stirredfor ˜10 min. The solid precipitate was collected, dried under vacuum,and recrystallized from toluene/hexanes to provide Part D compound (162mg; 90%) as a solid.

[0324] A mixture of Part D compound (174 mg; 0.543 mmol), glycine methylester hydrochloride (68 mg; 0.54 mmol) and Et₃N (72 μL; 0.54 mmol) inMeOH (4 mL) was stirred at RT for 5 h. The reaction mixture was cooledto 0° C. and NaBH₄ (20 mg; 0.54 mmol) was added portionwise (exothermicreaction). The reaction was allowed to warm to RT and stirred at RT for30 min, then partitioned between EtOAc and H₂O. The organic phase wasdried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 3:1 to 1:1 hexane:EtOAc)to give Part E compound (176 mg; 82%) as an oil.

[0325] A solution of Part E compound (25 mg; 0.063 mmol),4-methoxyphenyl chloroformate (12 mg; 0.065 mmol) and Et₃N (28 μL; 0.20mmol) in CH₂Cl₂ (1 mL) was stirred at RT for 30 min. The reaction wascomplete by TLC at this point. Volatiles were removed in vacuo and theresidue was dissolved in THF (1 mL) and aqueous LiOH (100 μL of a 1 Msolution) was added. The reaction was stirred at RT overnight, afterwhich volatiles were removed in vacuo. The residue was partitionedbetween EtOAc and excess aqueous 1M HCl. The organic phase was washedwith H₂O, dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified by preparative HPLC (from 70% A:30% B to 0% A:100% B(A=90%H₂O/10% MeOH+0.1% TFA);(B=90% MeOH/10% H₂O+0.1% TFA) for 30 min at 25ml/min; detection at 220 nm.; YMC ODS 30×250 mm column) to give thetitle compound (20 mg; 60%) as a solid. [M+H]⁺=531.3

[0326]¹H NMR (CDCl₃) δ 2.21 (2H, m), 2.33 (3H, s), 2.88 (2H, m), 3.78(3H, s), 4.05 (4H, m), 4.57-4.67 (2H, m), 6.85-6.91 (5H, m), 7.02-7.08(2H, m), 7.22-7.30 (2H, m), 7.39-7.48 (2H, m), 7.95-7.97 (2H, d, J=7.9Hz)

EXAMPLE 8

[0327]

[0328] A mixture of Example 7 Part C compound (150 mg; 0.51 mmol),3-hydroxybenzaldehyde (62 mg; 0.51 mmol) and K₂CO₃ (210 mg; 1.53 mmol)in DMF (1 mL) was heated at 100° C. in an oil bath for 2 h. At thispoint HPLC indicated that all starting material had been consumed. Thereaction was cooled to RT and poured into ice-water (20 mL) and stirredfor ˜10 min. The solid precipitate was collected, washed with cold water(2×5 mL), dried under vacuum, and recrystallized from toluene/hexanes toprovide to provide Part A compound (174 mg; 90%) as a solid.

[0329] A mixture of Part A compound (174 mg; 0.543 mmol), glycine methylester hydrochloride (68 mg; 0.54 mmol) and Et₃N (72 μL; 0.54 mmol) inMeOH (4 mL) was stirred at RT for 5 h. The reaction mixture was cooledto 0° C. and NaBH₄ (20 mg; 0.54 mmol) was added portionwise (exothermicreaction). The reaction was allowed to warm to RT and stirred at RT for30 min, then partitioned between EtOAc and H₂O. The organic phase wasdried (Na₂SO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 3:1 to 1:1 hexane:EtOAc)to give Part B compound (180 mg; 84%) as an oil.

[0330] A solution of Part B compound (25 mg; 0.063 mmol),4-methoxyphenyl chloroformate (12 mg; 0.065 mmol) and Et₃N (28 μL; 0.20mmol) in CH₂Cl₂ (1 mL) was stirred at RT for 30 min. The reaction wascomplete by TLC at this point. Volatiles were removed in vacuo and theresidue was dissolved in THF (1 mL) and aqueous LiOH (100 μL of a 1 Msolution) was added. The reaction was stirred at RT overnight, afterwhich volatiles were removed in vacuo. The residue was partitionedbetween EtOAc and excess aqueous 1M HCl. The organic phase was washedwith H₂O, dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified by preparative HPLC (from 70% A:30% B to 0% A:100% B(A=90%H₂O/10% MeOH+0.1% TFA);(B=90% MeOH/10% H₂O+0.1% TFA) for 30 min at 25ml/min; detection at 220 nm.; YMC ODS 30×250 mm column) to give thetitle compound (15 mg; 45%) as a solid.

[0331] [M+H]⁺=531.3

[0332]¹H NMR (CDCl₃): δ 2.21 (2H, m), 2.33 (3H, s), 2.88 (2H, t, J=7.5Hz), 3.78 (3H, s), 4.03 (4H, m), 4.57-4.67 (2H, m), 6.84-6.89 (5H, m),7.01-7.05 (2H, m), 7.29 (2H, m) 7.40-7.45 (2H, m), 7.94-7.96 (2H, d,J=7.9 Hz)

EXAMPLE 9

[0333]

[0334] To a solution of 4-formyl-2-phenylimidazole (100 mg, 0.58 mmol)in CH₂Cl₂ (2 mL) was added aqueous KOH (2 mL of a 30% solution),followed by dimethyl sulfate (66 μL, 0.70 mmol), and tetrabutylammoniumbromide (10 mg; 0.03 mmol). The reaction mixture was stirred overnightat RT and then was partitioned between EtOAc and water; the organicphase was washed with brine and then concentrated in vacuo. The residuewas chromatographed (SiO₂; continuous gradient from 1:1 hexane:EtOAc to100% EtOAc) to give 1-methyl-2-phenyl-imidazole-5-carboxaldehyde as asolid (45 mg; 42%; 1st product to elute; Part A compound) and theisomeric product Part B compound

[0335] (35 mg; 32%; 2^(nd) product to elute) as a solid.

[0336] To a solution of Part A compound (50 mg, 0.27 mmol) in MeOH (5mL) was added NaBH₄ (30 mg; 0.79 mmol). The mixture was stirred at RTfor 1 h, after which the reaction was quenched with excess saturatedaqueous NH₄Cl (5 mL). Volatiles were removed in vacuo, and the residuewas partitioned between saturated aqueous NaHCO₃ and EtOAc. The organicphase was washed with brine, dried (Na₂SO₄) and concentrated in vacuo togive Part C compound as a white solid (37 mg, 75%).

[0337] To a solution of (D)-4-hydroxyphenylglycine (20.0 g; 120 mmol) inMeOH (400 mL) was added dropwise chlorotrimethylsilane (30.4 mL; 240mmol). The reaction was stirred at RT for 74 h, then concentrated invacuo. To a solution of the residue in dioxane/H₂O (400 mL of a 1:1solution) were successively added NaHCO₃ (30.2 g; 359 mmol) and benzylchloroformate (18.8 mL; 132 mmol). The reaction was stirred at RT for 4h, then concentrated in vacuo. The residue was partitioned between H₂Oand EtOAc; the organic phase was washed with brine, dried (MgSO₄) andconcentrated in vacuo to give crude Part D compound (39.5 g). Thismaterial was recrystallized from hexane:EtOAc to give pure Part Dcompound (37.5 g; 99%) as white crystals.

[0338] To a solution of Part D compound (20 g; 63.5 mmol) in DMF (127mL) were successively added tert-butyldimethylsilyl chloride (14.4 g; 95mmol) and imidazole (6.50 g; 95 mmol). The reaction was s tirred at RTovernight, then partitioned between EtOAc and H₂O. The organic phase waswashed with H₂O and brine, dried (MgSO₄) and concentrated in vacuo. Theresidue was dissolved in THF (318 mL) and cooled to 0° C.; a solution oflithium borohydride (76.2 mL of a 2 M solution in THF; 152 mmol) wasadded dropwise. After addition was complete, the reaction mixture wasallowed to warm to RT and stirred at RT overnight, then quenched by slowaddition of excess MeOH. Volatiles were removed in vacuo to providecrude Part E compound.

[0339] To a 0° C. solution of crude Part E compound (theoretically 63.5mmol) in CH₂Cl₂ (212 mL) were successively added Et₃N (8.9 mL; 63.5mmol) and methanesulfonyl chloride (4.90 mL; 63.5 mmol). The reactionwas stirred at 0° C. for 1 h, then was partitioned between CH₂Cl₂ andaqueous 1N HCl. The organic phase was washed with brine, dried (MgSO4),then concentrated in vacuo to give the crude mesylate. This material wasdissolved in acetone (212 mL) and lithium bromide (9.0 g; 104 mmol) wasadded. The reaction mixture was stirred at 50° C. overnight, then cooledto RT and concentrated in vacuo. The residue was chromatographed (SiO₂;continuous gradient from 100% hexane to 100% EtOAc) to give Part Fcompound (1.15 g; 4% over 4 steps) as well as the deprotected phenol

[0340] 1.44 g; 7% over 4 steps)

[0341] To a −78° C. slurry of CuCN (650 mg; 7.26 mmol) in freshlydistilled dry THF (24.2 mL) under argon was added dropwiseisopropyllithium (20.4 mL of a 0.7 M solution in hexane; 14.5 mmol). Themixture was allowed to warm slowly to 0° C., at which point a clearsolution of the cyanocuprate reagent was obtained. The solution wascooled to −50° C. (cyclohexanone-dry ice bath) and Part F compound (1.12g; 2.42 mmol) in dry THF (6.9 mL) was added dropwise. The resultingmixture was allowed to warm from −50° C. to 10° C. over 4 h, thenquenched by slow addition of an aqueous solution of 9:1 saturatedaqueous NH4Cl:concentrated NH₄OH. The mixture was vigorously stirreduntil most of the solids had been dissolved, then partitioned betweenH₂O and EtOAc. The organic phase was washed with saturated aqueous NH₄Cland brine, dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (continuous gradient from 100% hexane to 100% EtOAc)togive Part G compound (317 mg; 31%) as a clear colorless oil.

[0342] A mixture of Part G compound (317 mg; 0.742 mmol) and 10% Pd/C(159 mg) in MeOH (3.7 mL) was stirred under an atmosphere of H₂(balloon) at RT for 3 h. The catalyst was filtered off (Celite) and thefiltrate was concentrated in vacuo. A solution of the resulting crudefree amine, Et₃N (114 μL; 0.81 mmol) and methyl bromoacetate (77 μL;0.81 mmol) in THF (9.3 mL) was stirred at RT overnight. The reactionmixture was partitioned between EtOAc and H₂O; the organic phase waswashed with brine, dried (MgSO₄) and concentrated in vacuo to providecrude Part H compound.

[0343] To a solution of the crude Part H compound from above (0.742 mmoltheoretically) and NaHCO₃ (125 mg; 1.48 mmol) in dioxane:H₂O (7.4 mL ofa 1:1 solution) was added 4-methoxyphenyl chloroformate (220 μL; 1.48mmol) dropwise. The reaction was stirred at RT for 2 h, then partitionedbetween EtOAc and H₂O. The organic phase was washed with aqueous 1N HCland brine, dried (MgSO₄) and concentrated in vacuo. The crudeTBS-protected phenol product was dissolved in THF (3 mL) andtetrabutylammonium fluoride (1 mL of a 1M solution in THF) was added.The reaction was stirred at RT for 1 h, after which it was partitionedbetween EtOAc and H₂O. The organic phase was washed with brine, dried(MgSO4) and concentrated in vacuo. The residue was purified bypreparative HPLC (continuous gradient from 70:30 A:B to 100% B;A=90:10:0.1H₂O:MeOH:TFA; B=90:10:0.1 MeOH:H₂O:TFA; 12 min run @ 20mL/min; detection at 220 nm; YMC ODS 20×100 mm column) to provide Part Icompound (117 mg; 39% over 4 steps) as an oil.

[0344] To a 65° C. solution of Part I compound (10 mg; 0.025 mmol), PartB compound (10 mg; 0.05 mmol) and Ph₃P (16 mg; 0.063 mmol) in toluene (2mL) was added dropwise diethyl azodicarboxylate (10 μL; 0.063 mmol). Thereaction was stirred at 65° C. for 2 days, then was partitioned betweenEtOAc/Hex (1:1) and water (15 mL each). The organic phase was dried(MgSO₄) and concentrated in vacuo. The residue was purified bypreparative HPLC (continuous gradient from 50:50 A:B to 100% B;A=90:10:0.1H₂O:MeOH:TFA; B=90:10:0.1 MeOH:H₂O:TFA) to give Part Jcompound (2.5 mg; 18%) as a solid.

[0345] A solution of Part J compound (2.5 mg; 0.0043 mmol) and LiOH.H₂O(1 mg; 0.024 mmol) in H₂O/THF was stirred at RT overnight, after whichvolatiles were removed in vacuo. The residue was partitioned betweenEtOAc and excess aqueous 1M HCl. The organic phase was washed with H₂O,dried (Na₂SO₄) and concentrated in vacuo. The residue was purified bypreparative HPLC (using the same conditions as for the purification ofPart J compound) to give the title compound (0.5 mg; 21%) as a solid.

[0346] [M+H]⁺=558.2

EXAMPLE 10

[0347]

[0348] To a solution of Example 9 Part B compound (136 mg, 0.73 mmol) inMeOH (10 mL) was added NaBH₄ (60 mg; 1.58 mmol). The mixture was stirredat RT for 1 h, after which the reaction was quenched with excesssaturated aqueous NH₄Cl (10 mL). Volatiles were removed in vacuo, andthe residue was partitioned between saturated aqueous NaHCO₃ and EtOAc.The organic phase was washed with brine, dried (Na₂SO₄) and concentratedin vacuo to give Part A compound as an oil (110 mg, 80%).

[0349] To a RT solution of 4-methoxybenzonitrile (13 g; 98 mmol) in THF(200 mL) under argon were successively added CuCl (250 mg; 2.5 mmol) andisobutyl magnesium bromide (50 mL of a 2 M solution in Et₂O; 100 mmol).The reaction mixture was heated at 60° C. for 2 h, then was cooled toRT. Lithium aluminum hydride (3.50 g; 18.4 mmol) was added portionwise,after which the reaction mixture was heated at 60° C. for a further 2 h,then was cooled to RT and stirred overnight at RT. The reaction wasquenched by slow dropwise addition of EtOAc (50 mL), then was stirred atRT for 2 h, followed by addition of THF (100 mL) and saturated aqueousNaHCO₃ (50 mL). The mixture was stirred at RT for 2 h, then wasfiltered. The residual solids were washed with EtOAc and the combinedfiltrates were concentrated in vacuo. The residue was partitionedbetween EtOAc (500 mL) and aqueous 1 N NaOH (200 mL). The organic phasewas dried (Na₂SO₄) and concentrated in vacuo to give crude Part Bcompound (19 g; 100%) as a yellow oil.

[0350] To a 0° C. solution of crude Part B compound (18 g; 93 mmol) inCH₂Cl₂ (200 mL) under argon was added dropwise BBr₃ (30 mL; 320 mmol).The reaction was allowed to slowly warm to RT and was stirred at RT for2 h, then was cooled to −78° C. CH₂Cl₂ (200 mL) was added, followed byslow dropwise addition of MeOH (30 mL). After addition was complete, themixture was allowed to warm slowly to RT, then cooled to 0° C.Additional MeOH (100 mL) was added cautiously, followed by 15% aqueousHCl (150 mL). Organic solvents were removed in vacuo to give ˜150 mL ofaqueous solution, which was cooled to 0° C. and cautiously basified withexcess concentrated ammonium hydroxide solution (until pH˜10). Theresultant white precipitate was washed successively with H₂O, THF andEtOAc and dried to give crude Part C compound (9.0 g; 54%) as a whitesolid.

[0351] To a solution of Part C compound (800 mg; 4.47 mmol) in THF/MeOH(20 mL of a 1:1 solution) were successively added Et₃N (1 mL; 6.4 mmol)and methyl bromoacetate (800 μL; 8.5 mmol). The reaction mixture wasstirred at RT for 2 h, at which point the reaction was −80% complete byanalytical HPLC. Saturated aqueous NaHCO₃ (2 mL) was then added,followed by dropwise addition of 4-methoxyphenyl chloroformate (1.10 mL;7.4 mmol). The reaction was stirred at RT for 30 min, after whichvolatiles were removed in vacuo. The residue was partitioned betweensaturated aqueous NaHCO₃ and Et₂O (100 mL). The organic phase was washedwith aqueous 1 N HCl and brine, dried (Na₂SO₄) and concentrated invacuo. The residue was chromatographed (SiO₂; continuous gradient from100% hexane to 100% EtOAc) to give Part D compound (400 mg; 27%) as awhite solid.

[0352] To a 65° C. solution of Part D compound (53 mg; 0.13 mmol), PartA compound (50 mg; 0.27 mmol) and Ph₃P (84 mg; 0.33 mmol) in toluene (6mL) was added dropwise diethyl azodicarboxylate (51 μL; 0.33 mmol). Thereaction was stirred at 65° C. for 2 days, then was partitioned betweenEtOAc/Hex (1:1) and water (25 mL each). The organic phase was dried(MgSO₄) and concentrated in vacuo. The residue was purified bypreparative HPLC (as for the purification of Example 9 Part J compound)to give the ester intermediate. This material was subjected to lithiumhydroxide-mediated hydrolysis (as for Example 9 compound) and the crudeproduct was purified by preparative HPLC (as for Example 9 compound PartJ compound) to provide the title compound (30 mg; 36%) as an oil.

[0353] [M+H]⁺=558.2

EXAMPLE 11

[0354]

[0355] A mixture of 4-phenyl imidazole (1.15 g; 8 mmol) and aceticanhydride (1.85 mL, 20 mmol) in toluene (6 mL) was heated at 80° C. for1.5 h. At this point a solution of iodomethane (1.25 mL; 20 mmol) intoluene (6 mL) was added and the reaction mixture was heated in a sealedtube at 140° C. overnight. Volatiles were removed in vacuo & the residuewas taken up in CH₂Cl₂ (40 mL). The insoluble material was filtered offand the filtrate was concentrated in vacuo. The residue waschromatographed (SiO2; continuous gradient from 99:1 to 95:5CH₂Cl₂:MeOH) to give Part A compound (650 mg; 51%) as a yellow solid.

[0356] To a −78° C. solution of Part A compound (650 mg; 4.11 mmol) inanhydrous THF (8.5 mL) was added dropwise n-BuLi (1.9 mL of a 2.5 Msolution in hexanes; 4.75 mmol). The reaction was stirred at −78° C. for15 min, after which ethylene oxide (3 mL; 580 mmol; liquefied by coolingin dry-ice/acetone) was added. The reaction mixture was graduallyallowed to warm to RT and stirred at RT overnight, then partitionedbetween water and Et₂O (60 mL each). The organic phase was washed withbrine (50 mL), dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 100% CH₂Cl₂ to 92:8CH₂Cl₂:MeOH) to provide Part B compound (200 mg; 24%) as a white solid.

[0357] To a 0° C. solution of Part B compound (30 mg; 0.15 mmol) andEt₃N (25 μL; 0.18 mmol) in CH₂Cl₂ (2 mL) was added dropwisemethanesulfonyl chloride (14 μL; 0.18 mmol). The reaction was stirred at0° C. for 30 min, after which TLC (hexane:EtOAc 1:1) indicated that thereaction was complete. Volatiles were removed in vacuo to give Part Ccompound (38 mg; 91%) which was used in the next step without furtherpurification.

[0358] A mixture of crude Part C compound (38 mg; 0.14 mmol), Example 9Part H compound (10 mg; 0.025 mmol) and K₂CO₃ (7 mg; 0.05 mmol) in MeCN(2 mL) was heated at reflux for 19 h. Volatiles were removed in vacuoand the residue was purified by preparative HPLC (from 50% A:50% B to100% B (A=90:10:0.1H₂O:MeOH:TFA; B=90:10:0.1 MeOH:H₂O:TFA) for 12 min at20 mL/min; detection at 220 nm; YMC ODS 20×100 mm column) to give Part Dcompound (9 mg; 61%) as a syrup.

[0359] A solution of Part D compound (9 mg; 0.015 mmol) and LiOH.H₂O (7mg; 0.15 mmol) in THF and H₂O (1 mL each) was stirred at RT for 44 h.The solution was acidified to pH 5 with aqueous 1 N HCl, then extractedwith EtOAc (3×). The combined organic extracts were concentrated invacuo and the residue was purified by preparative HPLC (as for Part Dcompound) to give, after lyophilization from dioxane, the title compound(6 mg; 68%) as a white solid.

[0360] [M+H]=572.3

EXAMPLE 12

[0361]

[0362] To a vigorously stirred mixture of chloroacetonitre (7.5 g; 0.10mmol) and hydroxylamine hydrochloride (6.95 g; 0.10 mmol) in H₂O (25 mL)was carefully added Na₂CO₃ (5.3 g; 0.05 mmol) while maintaining thereaction temperature at ≦30° C. The mixture was then stirred at 30° C.for 15 min, then was extracted with Et₂O (2×80 mL). The combined organicextracts were dried (Na₂SO₄) and concentrated in vacuo to give Part Acompound (6.9 g; 64%) as a white solid.

[0363] To a 0° C. mixture of Part A compound (1.0 g; 9.0 mmol) and K₂CO₃(870 mg; 6.3 mmol) in acetone (45 mL) was added dropwise a solution ofbenzoyl chloride (1.0 mL; 9.0 mmol) in acetone (5 mL). The reaction wasallowed to warm to RT and stirred at RT for 30 min. Volatiles wereremoved in vacuo and the residue was partitioned between H₂O and EtOAc.The organic phase was washed with brine, dried (Na₂SO₄) and concentratedin vacuo to give crude Part B compound (1.50 g; 76%) as a white solid.

[0364] A solution of crude Part B compound (1.50 g) in HOAc (25 mL) washeated to reflux for 1.5 h, after which volatiles were removed in vacuo.The residue was partitioned between H₂O (40 mL) and EtOAc (50 mL); theorganic phase was washed with H₂O (2×40 mL), saturated aqueous NaHCO₃(2×40 mL) and brine (40 mL), dried (MgSO₄) and concentrated in vacuo.The residue was chromatographed (SiO2; continuous gradient from 4:1 to7:3 hexane:EtOAc) to give Part C compound (840 mg; 61%) as a whitesolid.

[0365] A mixture of crude Part C compound (20 mg; 0.10 mmol), Example 9Part H compound (8 mg; 0.02 mmol) and K₂CO₃ (5 mg; 0.03 mmol) in MeCN (5mL) was heated at reflux for 1.5 h. Volatiles were removed in vacuo andthe residue was purified by preparative HPLC (continuous gradient from60:40 A:B to 100% B; A=90:10:0.1H₂O:MeOH:TFA; B=90:10:0.1 MeOH:H₂O:TFA;12 min run @ 20 mL/min; detection at 220 nm; YMC ODS 20×100 mm column)to give Part D compound (8 mg; 72%) as a syrup.

[0366] A solution of Part D compound (8 mg; 0.014 mmol) and LIOH.H₂O (3mg; 0.07 mmol) in THF (1 mL) and H₂O (0.5 mL) was stirred at RT for 24h. The solution was acidified to pH 5 with aqueous 1 N HCl, thenextracted with EtOAc (3×). The combined organic extracts wereconcentrated in vacuo and the residue was purified by preparative HPLC(same conditions as for Part D compound) to give the title compound (6mg; 77%) as a colorless syrup.

[0367] [M+H]⁺=546.2

EXAMPLE 13

[0368]

[0369] To a RT mixture of (S)-1-(4-methoxyphenyl)-ethylamine (5.45 g, 36mmol) in THF (50 mL) and aqueous NaHCO₃ (6.05 g in 25 mL H₂O) was addeddropwise benzyl chloroformate (6.20 mL; 43 mmol). The reaction wasstirred at RT for 30 min; the organic phase was isolated andconcentrated in vacuo. The residue was partitioned between EtOAc and H₂O(100 mL each); the organic phase was washed with brine, dried (MgSO₄),and concentrated in vacuo to about 30 mL volume. An equivalent volume ofhexane (30 mL) was added and Part A compound (9.12 g; 89%) crystallizedas colorless needles.

[0370] To a −78° C. solution of Part A compound (2.50 g; 8.8 mmol) inanhydrous CH₂Cl₂ (11 mL) was added dropwise a solution of BBr₃ in CH₂Cl₂(11.4 mL of a 1.0 M solution; 11.4 mmol) over 25 min. The reaction wasallowed to warm to 0° C. and stirred at 0° C. for 6 h, then quenchedcarefully at −78° C. by dropwise addition of excess MeOH (6 mL). Thesolution was allowed to warm to 0° C. and stirred at 0° C. for 5 min.The solution was partitioned between CH₂Cl₂ (60 mL) and H₂O (50 mL). Theorganic phase was washed successively with brine and 5% aqueous NaHCO₃(50 mL each), dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 4:1 to 1:1 hex:EtOAc) tofurnish Part B compound (1.30 g; 63% yield based on 650 mg (26%) ofrecovered unreacted Part A compound) as a white solid.

[0371] A mixture of tert-butyldimethylsilyl chloride (357 mg; 2.36mmol), Part B compound (535 mg; 1.97 mmol) and imidazole (161 mg; 2.36mmol) in DMF (5 mL) was stirred at RT for 2 h. The reaction waspartitioned between EtOAc (20 mL) and water (50 mL). The organic phasewas washed with water (2×50 mL), dried (Na₂SO₄), and concentrated invacuo. The residue was chromatographed (SiO₂; hex:EtOAc 3:1) to givePart C compound (320 mg; 42%) as an oil in addition to recoveredstarting phenol (150 mg; 20%).

[0372] A mixture of Part C compound (320 mg; 0.83 mmol) and 10%palladium on carbon (30 mg) in MeOH (30 mL) was stirred under anatmosphere of H₂ (balloon) at RT for 1 h, at which point the reactionwas complete by HPLC. The catalyst was filtered off through Celite® andthe filtrate was concentrated in vacuo to give Part D compound (230 mg)as a white solid which was used in the next step without furtherpurification.

[0373] A solution of Part D compound (230 mg), methyl bromoacetate (86μL; 0.91 mmol) and Et₃N (127 μL; 0.91 mmol) in THF (10 mL) was stirredat RT for 15 h. The reaction mixture was partitioned between H₂O andEtOAc (30 mL) each. The organic phase was washed with brine, dried(MgSO₄) and concentrated in vacuo. The residue was chromatographed(SiO₂; stepwise gradient from hex:EtOAc 9:1 to 1:1) to furnish Part Ecompound (177 mg; 66% over 2 steps) as an oil.

[0374] To a solution of Part E compound (9.0 g; 27.9 mmol), NaHCO₃ (4.70g; 55.8 mmol) in THF:H₂O (240 mL of a 1:1 solution) was added a solutionof 4-methoxyphenyl chloroformate (5.0 mL; 33.5 mmol) dropwise. Thereaction was stirred at RT for 2 h, then was partitioned between EtOAc(250 mL) and H₂O (200 mL). The organic phase was washed with brine (200mL), dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 9:1 to 7:3 hexane:EtOAc)to provide pure Part F compound (12.5 g; 95%).

[0375] To a solution of Part F compound (12.5 g; 26.4 mmol) in THF (100mL) was added dropwise tetrabutylammonium fluoride (32 mL of a 1 Msolution in THF; 32 mmol). The reaction was stirred at RT for 2 h, thenwas partitioned between EtOAc (250 mL) and H₂O (200 mL). The organicphase was washed with brine (200 mL), dried (MgSO₄) and concentrated invacuo. The residue was chromatographed (SiO₂; stepwise gradient from 9:1to 3:2 hex:EtOAc) to provide Part G compound (8.0 g; 84%) as a syrup.

[0376] A mixture of crude Example 12 Part C compound (20 mg; 0.10 mmol),Part G compound (8 mg; 0.02 mmol) and K₂CO₃, (5 mg; 0.03 mmol) in MeCN(5 mL) was heated at reflux for 1.5 h. Volatiles were removed in vacuoand the residue was purified by preparative HPLC (same conditions as forExample 12 Part D compound) to give Part H compound (8 mg; 72%) as asyrup.

[0377] A solution of Part H compound (8 mg; 0.014 mmol) and LiOH.H₂O (3mg; 0.07 mmol) in THF (1 mL) and H₂O (0.5 mL) was stirred at RT for 24h. The solution was acidified to pH 5 with aqueous 1 N HCl, thenextracted with EtOAc (3×). The combined organic extracts wereconcentrated in vacuo and the residue was purified by preparative HPLC(same conditions as for Example 12 Part D compound) to give the titlecompound (6 mg; 77%) as a colorless syrup.

[0378] [M+H]⁺=504.2

EXAMPLE 14

[0379]

[0380] To a 0° C. solution of ethyl propionylacetate (10.0 g, 69.4 mmol)in CHCL₃ (60 mL) was added dropwise a solution of Br₂ (3.6 mL; 69.4mmol) in CHCl₃ (20 mL) and the resulting mixture was stirred at 0° C.for 0.5 h. The reaction was allowed to warm to RT and stirred at RT for0.5 h. Air was then bubbled into the mixture for 1 h. Volatiles werethen removed in vacuo to yield an oily residue to provide crude Part Acompound (15.3 g,>95% yield) as an oil which was used in the nextreaction without further purification.

[0381] A mixture of Part A compound (400 mg; 1.79 mmol) and sodium azide(136 mg; 2.09 mmol) in acetone (6 mL) and H₂O (1 mL) was stirred at RTfor 1 h, then at 50° C. for 1 h. At this point analytical HPLC showedthat starting material had been consumed. Volatiles were removed invacuo and the residue was partitioned between H₂O and CH₂Cl₂. Theorganic phase was dried (MgSO₄) and concentrated in vacuo. The residuewas chromatographed (SiO₂; continuous gradient from hexane to 1:1hexane:EtOAc) to provide Part B compound (280 mg; 85%) as a pale yellowoil.

[0382] To a solution of Part B compound (100 mg; 0.54 mmol) in dioxane(4 mL) was added resin-bound Ph₃P (540 mg of 3 mmol/g resin; 3equivalents). The mixture was shaken for 10 min at RT. Benzoyl chloride(70 μL; 0.60 mmol) was added and the reaction mixture was heated at 75°C. for 2 h, at which point the reaction was complete by HPLC. Thereaction was filtered and the filtrate was concentrated in vacuo. Theresidue was chromatographed (SiO₂; continuous gradient from hexane to1:1 hexane:EtOAc) to provide Part C compound (62 mg; 50%) as a colorlessoil.

[0383] To a 0° C. solution of LiAlH₄ (1.0 mL of a 1 M solution; 1 mmol)was added dropwise a solution of Part C compound (75 mg; 0.031 mmol) inTHF. After 30 min at 0° C., the rection was quenched cautiously withH₂O, followed by addition of aqueous NaOH (2 mL of a 3N solution).Volatiles were removed in vacuo and the residue was partitioned betweenH₂O and CH₂Cl₂. The aqueous phase was extracted with CH₂Cl₂ (2×). Thecombined organic extracts were concentrated in vacuo and the residue waschromatographed (SiO₂; continuous gradient from 100% hexane to 100%EtOAc) to give Part D compound (55 mg; 89%) as a colorless oil.

[0384] To a 0° C. solution of Part D compound (20 mg; 0.098 mmol),Example 13 Part G compound (33 mg; 0.092 mmol) and Ph₃P (40 mg; 0.15mmol) in CH₂Cl₂(2 mL) was added a solution of DEAD (31 μL; 0.20 mmol)inCH₂Cl₂ (2 mL) dropwise. The reaction was allowed to warm to RT andstirred at RT overnight. Volatiles were removed in vacuo and the residuewas chromatographed (SiO₂; continuous gradient from 100% hexane to 100%EtOAc) to give Part E compound (32 mg; 61%) as a colorless oil.

[0385] A solution of Part E compound (16 mg; 0.029 mmol) in aqueous LiOH(0.5 mL of a 2N solution) and MeOH/THF (0.5 mL each) was stirred at RTfor 4 h. Organic solvents were removed in vacuo and the aqueous phasewas acidified to pH 2 with aqueous 1 N HCl. The resultant whiteprecipitate was collected by filtration and dried to give the titlecompound (9 mg; 60%) as a white solid.

[0386] [M+H]⁺=531.2

EXAMPLE 15

[0387]

[0388] A mixture of Example 13 Part G compound (3.5 g; 9.75 mmol),1,2-dibromoethane (4.2 mL; 49 mmol) and KCO₃ (2.2 g; 15.6 mmol) in MeCN(32.5 mL) was heated at 90° C. for 15 h. The mixture was cooled to RTand volatiles were removed in vacuo. The residue was partitioned betweenH₂O and EtOAc; the organic phase was washed with H₂O and brine, dried(MgSO₄) and concentrated in vacuo. The residue was chromatographed(SiO₂; continuous gradient from 100% hexane to 1:1 hexane:EtOAc over 45min; then 1:1 hexane:EtOAc to 100% EtOAc over 10 min) to provide Part Acompound (2.0 g; 44%; 66% based on recovered starting material) as anoil.

[0389] A mixture of Part A compound (2.0 g; 4.3 mmol) andtetrabutylammonium cyanide (3.5 g; 12.9 mmol) in CH₂Cl₂ (21.5 mL) wasstirred at RT for 2.5 h. Volatiles were removed in vacuo, and theresidue was chromatographed (SiO₂; continuous gradient from 100% hexaneto 1:1 hexane:EtOAc over 45 min, then 1:1 hexane:EtOAc to 100% EtOAcover 10 min) to provide Part B compound (1.49 g; 84%) as an oil.

[0390] A mixture of Part B compound (450 mg; 1.14 mmol) andhydroxylamine (230 mg of a 50% wt/wt aqueous solution) in MeOH:H₂O (8.4mL of a 2:1 solution) was heated ato 95° C. for 4 h. The reaction wascooled to RT and volatiles were removed in vacuo. The residue waspurified by preparative HPLC (continuous gradient from 70:30 A:B to 100%B for 25 min © 25 ml/min; A=90:10:0.1H2O:MeOH:TFA; B=90:10:0.1MeOH:H₂O:TFA; detection at 220 nm; YMC ODS 30×250 mm column; retentiontime=17.1 min) to provide Part C compound (390 mg; 77%) as an oil.

[0391] To a solution of Part C compound (43 mg; 0.097 mmol) in pyridine(970 μL) was added benzoyl chloride (100 μL; 0.86 mmol). The mixture wasstirred in a sealed tube at 115° C. for 3 h, then was cooled to RT andpartitioned between H₂O and EtOAc. The organic phase was washed with H2Oand brine, dried (MgSO₄) and concentrated in vacuo. The residue waspurified by preparative HPLC (continuous gradient from 60:40 A:B to 100%B for 25 min, then held at 100% B for 10 min at 25 mL/min; A=90:10:0.1H₂O:MeOH:TFA; B=90:10:0.1 MeOH:H₂O:TFA; detection at 220 nm; YMC ODS30×250 mm column; retention time=29.4 min) to provide Part D compound(12 mg; 23%) as an oil.

[0392] A solution of Part D compound (6 mg; 0.011 mmol) and LiOH.H₂O(2.4 mg; 0.06 mmol) in THF (2 mL) and H₂O (1 mL) was stirred at RTovernight. EtOAc was added and the mixture was acidified to pH 2 withaqueous 1 N HCl; the organic phase was washed with H₂O and brine, dried(MgSO₄) and concentrated in vacuo. The residue was purified bypreparative HPLC (from 70:30 A:B to 100% B for 10 min, then held at 100%B for 5 min at 20 mL/min; A=90:10:0.1H₂O:MeOH:TFA; B=90:10:0.1MeOH:H₂O:TFA; detection at 220 nm; YMC ODS 20×100 mm column; retentiontime=11.2 min) to give the title compound (4.0 mg; 68%) as an oil.

[0393] [M+H]⁺=518.2

[0394] EXAMPLES 16 to 17

[0395] The following phenyloxadiazole carbamate acids were synthesizedaccording to the synthetic sequence described for Example 15:

Example No. R [M + H]⁺ 16

602.2 17

532.2

EXAMPLE 18

[0396]

[0397] To a solution of Example 13 Part E compound (3.60 g; 11.1 mmol),NaHCO₃ (1.21 g; 14.4 mmol) in dioxane:H₂O (75 mL of a 2:1 solution) wasadded isobutyl chloroformate (1.87 mL; 14.4 mmol) dropwise. The reactionwas stirred at RT for 2 h, then partitioned between EtOAc and H₂O. Theorganic phase was washed with brine, dried (MgSO₄) and concentrated invacuo to provide the crude TBS-phenol carbamate. This material wasdissolved in THF (50 mL) and tetrabutylammonium fluoride (4.17 mL of a75% aqueous solution) was added. The reaction was stirred at RT for 40min, after which volatiles were removed in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 9:1 to 2:3 hexane:EtOAcover 40 min; then 2:3 hexane:EtOAc to 100% EtOAc over 15 min) to providePart A compound (3.0 g; 87% over 2 steps) as a solid.

[0398] A mixture of Part A compound (45 mg; 0.146 mmol), Example 12 PartC compound (XX mg; 0.292 mmol) and K₂CO₃ (40 mg; 0.292 mmol) in MeCN (1mL) was stirred at 90° C. overnight. After cooling to RT, the mixturewas partitioned between EtOAc and H O. The organic phase was washed withbrine, dried (MgSO₄) and concentrated in vacuo. The residue was purifiedby preparative HPLC (continuous gradient from 50:50 A:B to 100% B;A=90:10:0.1H₂O:MeOH:TFA; B=90:10:0.1 MeOH:H₂O:TFA; 10 min run @ 20mL/min with 5 min hold time; detection at 220 nm; YMC ODS 20×100 mmcolumn) to provide Part B compound as an oil.

[0399] A solution of Part B compound and LiOH.H₂O (18 mg; 0.44 mmol) inTHF (0.7 mL) and H₂O (0.35 mL) was stirred at 50° C. for 3 h. EtOAc wasadded and the mixture was acidified to ˜pH 2 with aqueous 1 N HCl; theorganic phase was washed with H₂O and brine, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC(continuous gradient from 60:40 A:B to 100% B for 10 min, then held at100% B for 5 min @ 20 mL/min; A=90:10:0.1H₂O:MeOH:TFA; B=90:10:0.1MeOH:H₂O:TFA; detection at 220 nm; YMC ODS 20×100 mm column; retentiontime=10.2 min) to give the title compound (48 mg; 73% over 2 steps) as asolid.

[0400] [M+H]⁺=454.2

EXAMPLE 19

[0401]

[0402] A mixture of Example 18 Part A compound (850 mg; 2.75 mmol) andα-chloroacetonitrile(0.348 mL; 5.50 mmol) and K₂CO₃ (760 mg; 5.50 mmol)in CH₃CN (9.2 mL) was stirred at 90° C. for 3 h, then was cooled to RTand partitioned between EtOAc (95 mL) and H₂O (45 mL). The organic phasewas washed with brine (100 mL), dried (MgSO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; continuous gradient from 100% hexto 100% EtOAc) to give Part A compound (910 mg; 95%) as a colorless oil.

[0403] A mixture of Part A compound (910 mg; 2.61 mmol) andhydroxylamine (517 mg of a 50% solution in water; 7.83 mmol) in MeOH(11.6 mL) and H₂O (5.8 mL) was stirred at 95° C. for 6 h, then wascooled to RT and stirred at RT for another 6 h, after which volatileswere removed in vacuo. The residue was partitioned between EtOAc (120mL) and H₂O (65 mL). The organic phase was washed with brine (20 mL),dried (MgSO₄) and concentrated in vacuo to provide crude Part B compound(901 mg; 91%) as an oil, which was used in the next step without furtherpurification.

[0404] A mixture of Part B compound (56 mg; 0.147 mmol) and p-toluoylchloride (38.9 μL; 0.294 mmol) in pyridine (1.4 mL) was shaken at 110°C. for 14 h, after which the reaction mixture was cooled to RT andpartitioned between EtOAc (10 mL) and H₂O (5 mL). The organic phase waswashed with brine (20 mL), and concentrated in vacuo; the residue waspurified by preparative HPLC (as described for Example 15 Part Ecompound except that a continuous gradient from 50:50 Solvent A:SolventB to 100% B over 10 min was used, followed by 4 min hold at 100% B) togive Part C compound (12.6 mg; 18%) as an oil.

[0405] A solution of Part C compound (12.6 mg; 0.0262 mmol) and LiOH.H₂O(30.8 mg; 0.735 mmol) in THF (1 mL) and H₂O (0.5 mL) was stirred at RTfor 15 h, after which the mixture was acidified to pH 2 with aqueous 1 NHCl. The mixture was partitioned between EtOAc (10 mL) and H₂O (5 mL).The organic phase was washed with brine (20 mL), dried (MgSO₄) andconcentrated in vacuo; the residue was purified by preparative HPLC (asdescribed for Example 15 Part E compound except that a continuousgradient from 40:60 Solvent A:Solvent B to 100% B over 10 min was used,followed by 4 min hold at 100% B) to give the title compound (8.8 mg;72%) as an oil.

[0406] [M+H]⁺=468.0

EXAMPLES 20-47

[0407] Examples 20-47 were prepared in a similar fashion to Example 19(from Example 19 Part B compound) using a variety of appropriate acidchlorides.

Example # R [M + H]⁺ 20

488.2 21

490.3 22

510.2 23

522.2 24

538.1 25

590.2 26

468.2 27

522.1 28

538.3 29

468.1 30

468.1 31

482.1 32

484.1 33

484.1 34

484.0 35

498.1 36

498.1 37

502.1 38

522.0 39

471.8 40

472.0 41

479.2 42

482.2 43

482.1 44

498.1 45

498.1 46

514.1 47

530.0

EXAMPLE 48

[0408]

[0409] A mixture of Example 13 Part E compound (203 mg; 0.628 mmol),methyl chloroformate (0.063 mL; 0.817 mmol) and NaHCO, (69 mg; 0.817mmol) in dioxane:H₂O (3.14 mL of a 2:1 solution) was stirred at RT for14 h, after which the reaction was partitioned between EtOAc (10 mL) andH₂O (5 mL). The organic phase was washed with brine (10 mL), dried(MgSO₄) and concentrated in vacuo to give crude Part A compound whichwas used in the next step without further purification.

[0410] A solution of crude Part A compound and (n-Bu)₄NF (237 μL; 0.817mmol) in THF (2 mL) was stirred at RT for 30 min, after which volatileswere removed in vacuo. The residue was chromatographed (SiO₂; continuousgradient from 9:1 hex:EtOAc to 100% EtOAc) to give Part B compound (124mg; 74% for two steps) as a colorless oil.

[0411] A mixture of Part B compound (14.5 mg; 0.0543 mmol), Example 12Part C compound ((13.7 mg; 0.0706 mmol) and K₂CO₃ (9.8 mg; 0.0706 mmol)in CH₃CN (1 mL) was shaken at 88° C. for 14 h, then was cooled to RT andpartitioned between EtOAc (10 mL) and H₂O (5 mL). The organic phase waswashed with brine (20 mL) and concentrated in vacuo to give crude Part Ccompound, which was used in the next step without further purification.

[0412] A solution of crude Part C compound and LIOH.H₂O (6.8 mg; 0.163mmol) in THF (1 mL) and H₂O (0.5 mL) was stirred at RT for 16 h, afterwhich the mixture was acidified to pH 2 with aqueous 1 N HCl. Themixture was partitioned between EtOAc (10 mL) and H₂O (5 mL). Theorganic phase was washed with brine (20 mL), dried (MgSO₄) andconcentrated in vacuo; the residue was purified by preparative HPLC (asdescribed for Example 15 Part E compound except that a continuousgradient from 40:60 Solvent A:Solvent B to 100% B over 10 min was used,followed by 4 min hold at 100% B) to give the title compound (15.5 mg;69% for two steps) as an oil.

[0413] [M+H]⁺=412.2

EXAMPLES 49-53

[0414] Examples 49-53 were prepared using the same sequence as for thesynthesis of Example 48 (from Example 13 part E compound) usingappropriate chloroformates (instead of methyl chloroformate as forExample 48).

Example No. R [M + H]⁺ 49

426.2 50

440.3 51

440.4 52

454.2 53

481.2

EXAMPLE 54

[0415]

[0416] A mixture of Example 18 Part A compound (1000 mg; 3.24 mmol) and1,2-dibromoethane(1.7 mL; 19.4 mmol) and K₂CO₃ (896 mg; 6.48 mmol) inCH₃CN (9.2 mL) was stirred at 90° C. for 41 h, then was cooled to RT andpartitioned between EtOAc (100 mL) and H₂O (50 mL). The organic phasewas washed with brine (100 mL), dried (MgSO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; continuous gradient from 100% hexto 100% EtOAc) to give Part A compound (868 mg; 65%) as a colorless oil.

[0417] A mixture of Part A compound (868 mg; 2.09 mmol) andtetrabutylammonium cyanide (1.68 g; 6.27 mmol) in CH₂Cl₂(10.5 mL) wasstirred at RT for 15 h, after which volatiles were removed in vacuo; theresidue was chromatographed (SiO₂; continuous gradient from 100% hex to100% EtOAc) to give Part B compound (730 mg; 96%) as a colorless oil.

[0418] A mixture of Part B compound (730 mg; 2.02 mmol) andhydroxylamine (400 mg of a 50% solution in water; 6.06 mmol) in MeOH(9.0 mL) and H₂O (4.5 mL) was stirred at 95° C. for 4 h, after whichvolatiles were removed in vacuo. The residue was partitioned betweenEtOAc (120 mL) and H₂O (65 mL). The organic phase was washed with brine(70 mL), dried (MgSO₄) and concentrated in vacuo to provide crude Part Ccompound (750 mg; 94%) as an oil.

[0419] To a solution of Part C compound (50 mg; 0.127 mmol) in pyridine(1.3 mL) was added benzoyl chloride (29.5 μL; 0.254 mmol). The mixturewas shaken at 110° C. for 15 h, then was cooled to RT and partitionedbetween EtOAc (10 mL) and H₂O (5 mL). The organic phase was washed withbrine (20 mL), and concentrated in vacuo to give crude Part D compound,which was used in the next step without further purification.

[0420] To a solution of crude Part D compound and LiOH.H₂O (26.6 mg;0.635 mmol) in THF (0.8 mL) and H₂O (0.4 mL) was stirred at RT for 25 h,after which the mixture was acidified to pH 2 with aqueous 1 N HCl. Themixture was partitioned between EtOAc (10 mL) and H₂O (5 mL). Theorganic phase was washed with brine (20 mL), dried (MgSO₄) andconcentrated in vacuo; the residue was purified by preparative HPLC (asdescribed for Example 15 Part E compound except that a continuousgradient from 40:60 Solvent A:Solvent B to 100% B over 10 min was used,followed by 4 min hold at 100% B) to give the title compound (6.5 mg;11% for two steps) as an oil.

[0421] [M+H]⁺=468.1

EXAMPLES 55-65

[0422] Examples 55-65 were prepared using the analogous sequence for thesynthesis of Example 54 (starting from Example 54 Part C compound), butusing a variety of appropriate acid chlorides instead of benzoylchloride.

Example No. R [M + H]⁺ 55

482.1 56

482.2 57

502.1 58

524.2 59

536.1 60

536.2 61

552.0 62

552.1 63

482.1 64

496.2 65

516.2

EXAMPLE 66

[0423]

[0424] A mixture of 4-hydroxybenzaldehyde (5.2 g; 42.6 mmol),α-chloroacetonitrile(4.0 mL; 63.2 mmol) and K₂CO₃ (6.7 g; 48.5 mmol) inCH₃CN (106.5 mL) was stirred at 90° C. for 5 h, then was cooled to RTand partitioned between EtOAc (200 mL) and H₂O (110 mL). The organicphase was washed with brine (200 mL), dried (MgSO₄) and concentrated invacuo to provide crude Part A compound, which was used in the next stepwithout further purification.

[0425] A mixture of crude Part A compound and glycine methylesterhydrochloride(5.9 g; 46.9 mmol) and Et₃N (6.5 mL; 46.9 mmol) and 4Amolecular sieves (2 g) in MeOH (142 mL) was stirred at RT for 13 h,after which NaBH₄ (1.8 g; 46.9 mmol) was slowly added. The mixture wasstirred at RT for 1 h, after which volatiles were removed in vacuo. Theresidue was partitioned between EtOAc (150 mL) and H₂O (80 mL). Theorganic phase was washed with brine (150 mL), dried (MgSO₄) andconcentrated in vacuo to give Part B compound (6.0 g; 60% for two steps)as a colorless oil.

[0426] C.

[0427] A mixture of Part B compound (2.1 g; 8.97 mmol), isobutylchloroformate (1.52 mL; 11.7 mmol) and NaHCO₃ (983 mg; 11.7 mmol) indioxane:H₂O (60 mL of a 2:1 solution) was stirred at RT for 2 h, thenwas partitioned between EtOAc (120 mL) and H₂O (70 mL). The organicphase was washed with brine (140 mL), dried (MgSO₄) and concentrated invacuo. The residue was chromatographed (SiO₂; continuous gradient from100% hex to 100% EtOAc) to give Part C compound (2.84 g; 95%) as acolorless oil.

[0428] A mixture of Part C compound (1.7 g; 5.09 mmol) and hydroxylamine(1.0 g of a 50% solution in water; 15.27 mmol) in MeOH (22.6 mL) and H₂O(11.3 mL) was stirred at 95° C. for 5 h, after which volatiles wereremoved in vacuo. The residue was partitioned between EtOAc (140 mL) andH₂O (80 mL). The organic phase was washed with brine (20 mL), dried(MgSO₄) and concentrated in vacuo to provide crude Part D compound (1.77g; 95%) as an oil, which was used in the next step without furtherpurification.

[0429] To a solution of Part D compound (50 mg; 0.136 mmol) in solutionof pyridine (1.1 mL) was added p-toluoyl chloride (42.1 μL; 0.272 mmol).The mixture was shaken at 115° C. for 6 h, then was concentrated invacuo; the residue was purified by preparative HPLC (as described forExample 15 Part E compound except that a continuous gradient from 40:60Solvent A:Solvent B to 100% B over 10 min was used, followed by 4 minhold at 100% B) to give Part E compound (7.6 mg; 12%) as an oil.

[0430] A solution of Part E compound (7.6 mg; 0.0163 mmol) and LiOH.H₂O(28.5 mg; 0.68 mmol) in THF (0.86 mL) and H₂O (0.43 mL) was stirred atRT for 25 h, after which the reaction mixture was acidified to pH 2 withaqueous 1 N HCl. The mixture was partitioned between EtOAc (10 mL) andH₂O (5 mL). The organic phase was washed with brine (20 mL), dried(MgSO₄) and concentrated in vacuo; the residue was purified bypreparative HPLC (as described for Example 15 Part E compound exceptthat a continuous gradient from 40:60 Solvent A:Solvent B to 100% B over10 min was used, followed by 4 min hold at 100% B) to give the titlecompound (4.5 mg; 61%) as an oil.

[0431] [M+H]⁺=454.4

EXAMPLES 67-75

[0432] Examples 67-75 were prepared using the same sequence as for thesynthesis of Example 66 (starting from Example 66 Part D compound) usinga variety of appropriate acid chlorides (instead of p-toluoyl chloride).

Example No. R [M + H]⁺ 67

470.0 68

470.0 69

484.4 70

496.1 71

524.1 72

524.1 73

440.0 74

468.1 75

487.9

Example 76

[0433]

[0434] A mixture of(R)-(+)-{1-[4-(tert-butyl-dimethyl-silyloxy)-phenyl]-ethylamino}-aceticacid methyl ester [2.8 g; 8.67 mmol; obtained from(R)-(+)-1-(4-methoxy-phenyl)-ethylamine according to the proceduredescribed for the synthesis of Example 13 Part E compound] and isobutylchloroformate (1.5 mL; 11.3 mmol) and NaHCO₃ (0.95 g; 11.3 mmol) indioxane:H₂O (58 mL of a 2:1 solution) was stirred at RT for 1 h, afterwhich the reaction was partitioned between EtOAc (170 mL) and H₂O (90mL). The organic phase was washed with brine (140 mL), dried (MgSO₄) andconcentrated in vacuo to give crude Part A compound, which was used inthe next step without further purification.

[0435] To a solution of crude Part A compound in THF (28.9 mL) was added(n-Bu)₄NF (9.54 mL of a 1 M solution in THF; 9.54 mmol). The mixture wasstirred at RT for 45 min, then was partitioned between EtOAc (150 mL)and H₂O (70 mL). The organic phase was washed with brine (140 mL), dried(MgSO₄) and concentrated in vacuo to give Part B compound (2.4 g; 90%for 2 steps) as a colorless oil.

[0436] A mixture of Part B compound (46 mg; 0.149 mmol), Example 12 PartC compound ((37.8 mg; 0.194 mmol) and K₂CO₃ (26.8 mg; 0.194 mmol) inCH₃CN (2 mL) was stirred at 90° C. for 16 h, after which the reactionmixture was cooled to RT and partitioned between EtOAc (18 mL) and H₂O(8 mL). The organic phase was washed with brine (20 mL), andconcentrated in vacuo; the residue was purified by preparative HPLC (asdescribed for Example 15 Part E compound except that a continuousgradient from 50:50 Solvent A:Solvent B to 100% B over 10 min was used,followed by 4 min hold at 100% B) to give Part C compound (48.3 mg; 69%)as an oil.

[0437] D.

[0438] A solution of Part C compound (48.3 mg, 0.103 mmol) and LIOH.H₂O(18.8 mg; 0.447 mmol) in THF (1.2 mL) and H₂O (0.6 mL) was stirred at RTfor 15 h, then was acidified to pH 2 with aqueous 1 N HCl. The mixturewas partitioned between EtOAc (14 mL) and H₂O (8 mL). The organic phasewas washed with brine (15 mL), dried (MgSO₄) and concentrated in vacuo;the residue was purified by preparative HPLC (as described for Example15 Part E compound except that a continuous gradient from 40:60 SolventA:Solvent B to 100% B over 10 min was used, followed by 4 min hold at100% B) to give the title compound (40.3 mg; 86%) as an oil.

[0439] [M+H]⁺=454.0

EXAMPLE 77

[0440]

[0441] A mixture of Example 76 Part B compound (1.2 g; 3.88 mmol),α-chloroacetonitrile(0.49 mL; 7.76 mmol) and K₂CO₃ (1.07 g; 7.76 mmol)in CH₃CN (12.9 mL) was stirred at 90° C. for 10 h, then was cooled to RTand partitioned between EtOAc (95 mL) and H₂O (45 mL). The organic phasewas washed with brine (100 mL), dried (MgSO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; continuous gradient from 100% hexto 3:2 hex:EtOAc) to give Part A compound (1.17 g; 87%) as a colorlessoil.

[0442] A solution of Part A compound (1.17 g; 3.36 mmol) andhydroxylamine (0.65 g of a 50% solution in water; 9.7 mmol) in MeOH(17.2 mL) and H₂O (8.6 mL) was stirred at 95° C. for 6 h, then wascooled to RT and concentrated in vacuo. The residue was partitionedbetween EtOAc (140 mL) and H₂O (80 mL). The organic phase was washedwith brine (80 mL), dried (MgSO₄) and concentrated in vacuo to providecrude Part B compound (1.19 g; 93%) as an oil, which was used in thenext step without further purification.

[0443] To a solution of Part B compound (40 mg; 0.105 mmol) in pyridine(1.0 mL) was added p-toluoyl chloride (32.5 mg; 0.21 mmol). The mixturewas shaken at 115° C. for 6 h, then was cooled to RT and concentrated invacuo; the residue was purified by preparative HPLC (as described forExample 15 Part E compound except that a continuous gradient from 40:60Solvent A:Solvent B to 100% B over 10 min was used, followed by 4 minhold at 100% B) to give Part E compound (5.3 mg; 10%) as an oil.

[0444] A solution of Part C compound (5.3 mg; 0.011 mmol) and LiOH.H₂O(17.6 mg; 0.42 mmol) in THF (0.80 mL) and H₂O (0.40 mL) was shaken at50° C. for 6 h, then was cooled to RT and acidified to pH 2 with aqueous1 N HCl. The mixture was partitioned between EtOAc (10 mL) and H₂O (5mL). The organic phase was washed with brine (10 mL), dried (MgSO₄) andconcentrated in vacuo; the residue was purified by preparative HPLC (asdescribed for Example 15 Part E compound except that a continuousgradient from 40:60 Solvent A:Solvent B to 100% B over 10 min was used,followed by 4 min hold at 100% B) to give the title compound (2.9 mg;56%) as an oil.

[0445] [M+H]⁺=468.0

EXAMPLES 78-83

[0446] Examples 78-83 were prepared using the same sequence as for thesynthesis of Example 77 (from Example 77 Part B compound) using avariety of appropriate acid chlorides (instead of p-toluoyl chloride).

Example No. R [M + H]⁺ 78

537.9 79

482.0 80

484.0 81

498.0 82

510.0 83

502.2

EXAMPLE 84

[0447]

[0448] A mixture of methyl 4-chloroacetoacetate (400 mg; 2.6 mmol) andsodium azide (136 mg; 2.1 mmol) in acetone (6 mL) was diluted with H₂O(˜1 mL) until the azide had dissolved. The mixture was heated at 50° C.for 1 h, stirred overnight at RT, then was heated at 50° C. for 2 h. Thereaction was cooled to RT and the acetone was removed in vacuo. Theaqueous phase was extracted with CH₂Cl₂; the combined organic extractswere dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 100% hex to 3:2hex:EtOAc) to give Part A compound (237 mgs; 72%).

[0449] A mixture of Part A compound (237 mg; 1.51 mmol) and resin-boundPh₃P (1.56 g of 3 mmol/g resin; 4.68 mmol) in dioxane (5 mL) was shakenfor 10 min at RT. Benzoyl chloride (263 mg; 1.87 mmol) was then addedand the reaction was heated at 75° C. for 2 h, then cooled to RT andfiltered. The filtrate was concentrated in vacuo and the residue waschromatographed (SiO₂; continuous gradient from 100% hex to 1:1hex:EtOAc; compound was pre-loaded onto the column with Celite®) to givePart B compound (95 mg; 28%) as a pale yellow oil.

[0450] A solution of LiAlH₄ in THF (2.0 mL of a 1 M solution; 2.0 mmol)was added dropwise to Part B compound (95 mg; 0.44 mol) at RT. Thereaction was stirred overnight at RT, then was cooled to 0° C. andquenched cautiously with H₂O. Aqueous 3 N NaOH was added and the mixturewas concentrated in vacuo. The residue was partitioned between CH₂Cl₂and H₂O. The aqueous phase was extracted with CH₂Cl₂; the combinedorganic extracts were dried (Na₂SO₄) and concentrated in vacuo. Theresidue was chromatographed (SiO₂; continuous gradient from 100% hex to100% EtOAc; compound preloaded onto column with CH₂Cl₂) to provide PartC compound (100 mg; 100%) as a colorless oil.

[0451] Part D compound was synthesized from(S)-1-(3-methoxyphenyl)-ethylamine using the identical sequence as forthe synthesis of Example 13 Part G compound from(S)-1-(4-methoxyphenyl)-ethylamine.

[0452] A mixture of Part C compound (20 mg; 0.106 mmol), Part D compound(35 mg; 0.098 mmol) and cyanomethylene tributylphosphorane (70 μL; 0.29mmol) in toluene (1.5 mL) at 70° C. was shaken overnight, then wasconcentrated in vacuo. The residue was chromatographed (SiO₂; continuousgradient from 100% hex to 2:3 hex:EtOAc) to give a 2:1 mixture of Part Ecompound and unreacted Part D compound (37 mg; 55%) as a yellow oil.

[0453] [M+H]⁺=531.3

[0454] The mixture obtained in Part E (37 mg; 0.052 mmol) in a 1:1:1mixture of 2N solution of LiOH.H₂O, MeOH and THF(1.5 mL) was stirred atRT for 2 h, then was concentrated in vacuo. The resulting aqueoussolution was acidified to pH ˜3 with 1N aqueous HCl and extracted withCH₂Cl₂ (3×1 mL). The combined organic extracts were concentrated invacuo and the residue was purified by preparative HPLC (as for thepurification of Example 26) to give the title compound (10 mg; 26%) as asolid.

[0455] [M+H]⁺=517.20

EXAMPLE 85

[0456]

[0457] Example 84 Part C (20 mg; 0.106 mmol) compound was reacted withExample 13 Part G compound (35 mg; 0.098 mmol)

[0458] in the same way as described in Example 84 Part E to give a 2:1mixture of Part A compound and Example 13 Part G compound (30 mg, 57%).

[0459] [M+H]⁺=531.26

[0460] The title compound was obtained by the hydrolysis of the mixtureobtained in part A (30 mg) (as described in Example 84 Part F) toprovide part B. compound (13 mg, 43%).

[0461] [M+H]⁺=517.20

EXAMPLE 86

[0462]

[0463] To a 0° C. solution of ethyl propionylacetate (10.0 g, 69.4 mmol)in CHCl₃ (60 mL) was added dropwise a solution of Br₂ (3.6 mL; 69.4mmol) in CHCl₃ (20 mL) and the resulting mixture was stirred at 0° C.for 0.5 h. The reaction was allowed to warm to RT and stirred at RT for0.5 h. Air was then bubbled into the mixture for 1 h. Volatiles werethen removed in vacuo to yield an oily residue to provide crude Part Acompound (15.3 g,>95% yield) as an oil which was used in the nextreaction without further purification.

[0464] A mixture of Part A compound (400 mg; 1.79 mmol) and sodium azide(136 mg; 2.09 mmol) in acetone (6 mL) and H₂O (1 mL) was stirred at RTfor 1 h, then at 50° C. for 1 h. Analytical HPLC indicated that thestarting material had been consumed at this point. The acetone wasremoved in vacuo and the aqueous phase was extracted with CH₂Cl₂. Thecombined organic extracts were dried (MgSO₄) and concentrated in vacuo;the residue was chromatographed (SiO₂; continuous gradient from 100% hexto 1:1 hex:EtOAc) to give Part B compound (280 mg; 85%) as a pale yellowoil.

[0465] A mixture of Part B compound (100 mg; 0.54 mmol) and resin-boundPh₃P (540 mg of 3 mmol/g resin; 1.62 mmol) in dioxane (4 mL) was shakenfor 10 min at RT. Benzoyl chloride (84 mg; 0.60 mmol) was then added andthe reaction was heated at 75° C. for 2 h, then cooled to RT andfiltered. The filtrate was concentrated in vacuo and the residue waschromatographed (SiO₂; continuous gradient from 100% hex to 1:1hex:EtOAc; the compound was pre-loaded onto the column with Celite®) togive Part C compound (280 mg; 85%) as a pale yellow oil.

[0466] A solution of LiAlH₄ in THF (1 mL of a 1 M solution; 1 mmol) wasadded dropwise to Part C compound (75 mg; 0.30 mol) at 0° C. Thereaction was warmed to RT and stirred overnight at RT, then was cooledto 0° C. and quenched cautiously with H₂O. Aqueous 3 N NaOH was addedand the mixture was concentrated in vacuo. The residue was partitionedbetween CH₂Cl₂ and H₂O. The aqueous phase was extracted with CH₂Cl₂; thecombined organic extracts were dried (Na₂SO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; continuous gradient from 100% hexto 100% EtOAc; compound preloaded onto column with CH₂Cl₂) to providePart D compound (55 mg; 89%) as a colorless oil.

[0467] A mixture of Part D compound (20 mg; 0.100 mmol), Example 84 PartD compound (35 mg; 0.098 mmol)

[0468] and cyanomethylene tributylphosphorane (70 μL; 0.29 mmol) intoluene (500 μL) at 70° C. was shaken overnight, then was concentratedin vacuo. The residue was chromatographed (SiO₂; continuous gradientfrom 100% hex to 2:3 hex:EtOAc) to give a 4:1 mixture of Part E compoundand Example 84 Part D compound (32 mg; 55%) as a yellow oil.

[0469] [M+H]⁺=545.26

[0470] The mixture obtained in Part E (32 mg; 0.053 mmol) in a 1:1:1mixture of 2N solution of LiOH.H₂O, MeOH and THF(1.5 mL) was stirred atRT for 2 h, then was concentrated in vacuo. The resulting aqueoussolution was acidified to pH ˜3 with 1N aqueous HCl and extracted withDCM (3×1 mL). The combined organic extracts were concentrated in vacuoand purified by preparative HPLC (as for the purification of Example 26)to give the title compound (22 mg; 68%) as a solid.

[0471] [M+H]⁺=531.20

EXAMPLE 87

[0472]

[0473] To a solution of 3-hydroxybenzaldehyde (2 g; 16.3 mmol) in DMF(20 mL) was added t-butyldimethylsilyl chloride (2.9 g; 19.6 mmol) andimidazole (1.33 g; 19.6 mmol) at RT. The solution was stirred for 2 h atRT, then was partitioned between CH₂Cl₂ (40 mL) and aqueous 1 N NaOH.The organic layer was dried (MgSO₄) and concentrated in vacuo. Theresidue was chromatographed (SiO₂; 9:1 hexane:EtOAc) to give Part Acompound (2.3 g; 59%) as an oil.

[0474] To a solution of Part A compound (2.3 g; 9.7 mmol) in CH₂Cl₂ (20mL) was added 3-trifluoromethoxy-aniline (1.88 g; 10.7 mmol), NaBH(OAc)₃(2.4 g; 11.8 mmol) and glacial HOAc (2 mL) at RT. The solution wasstirred for 3 h, then was partitioned between CH₂Cl₂ (20 mL) andsaturated aqueous NaHCO₃. The organic layer was dried (MgSO₄) andconcentrated in vacuo to give crude Part B compound, which was used inthe next step without further purification.

[0475] A mixture of crude Part B compound, methyl bromoacetate (4.0 g;26 mmol) and K₂CO₃ (1.6 g; 11.8 mmol) in MeCN (20 mL) was stirred for 18h at 90° C., then was cooled to RT and concentrated in vacuo. Theresidue was partitioned between EtOAc and brine. The organic layer wasdried (MgSO₄) and concentrated in vacuo to give crude Part C compound asa yellow residue, which was used in the next step without furtherpurification.

[0476] A solution of crude Part C compound in THF (10 mL) andtetrabutylammonium fluoride (15 mL of a 1 M solution in THF; 15 mmol)was stirred at RT for 1 h and concentrated in vacuo. The residue waschromatographed (SiO₂; 4:1 hexane:EtOAc) to give Part D compound (1.2 g;35%) as an oil.

[0477] A mixture of Part D compound (20 mg; 0.05 mmol), Example 12 PartC compound (21 mg; 0.11 mmol)

[0478] and K₂CO₃ (15 mg; 0.11 mmol) in MeCN (5 mL) was stirred for 12 hat 80° C., then was cooled to RT and concentrated in vacuo to give thecrude Part E compound, which was used in the next step without furtherpurification.

[0479] A solution of crude Part E compound in MeOH (2 mL) and 1 Naqueous KOH (1 mL); the solution was stirred for 2 h at RT, then wasneutralized with 1N aqueous HCl and concentrated in vacuo. The residuewas purified by HPLC (YMC reverse-phase ODS 20×100 mm column; flowrate=20 mL/min; 10 min continuous gradient from 30:70 B:A to 100% B+5min hold-time at 100% B, where solvent A=90:10:0.1H₂O:MeOH:TFA andsolvent B=90:10:0.1 MeOH:H₂O:TFA) to give the title Compound (4 mg; 14%)as a solid.

[0480] [M+H]⁺=500.4

EXAMPLE 88

[0481]

[0482] A mixture of Example 87 Part D compound (0.1 g; 0.28 mmol),1,2-dibromoethane (5 mL; 12.2 mmol) and K₂CO₃ (0.38 g; 0.28 mmol) n MeCN(20 mL) was stirred for 20 h at 90° C., then was cooled to RT andconcentrated in vacuo. The residue was partitioned between EtOAc andbrine. The organic layer was dried (MgSO₄) and concentrated in vacuo togive crude Part A compound as a yellow oil, which was used in the nextstep without further purification.

[0483] A solution of crude Part A compound and tetrabutylammoniumnitrile (75 mg; 0.28 mmol) in CH₂Cl₂ (10 mL) was stirred at RT for 18 hand concentrated in vacuo. The residue was chromatographed (SiO₂; 9:1hexane:EtOAc) to give Part B compound (70 mg; 61%) as an oil.

[0484] To a solution of Part B Compound (55 mg; 0.13 mmol) in MeOH (2mL) was added hydroxylamine (17 mg of a 50% solution in water; 0.53mmol) at RT. The solution was stirred for 18 h at RT and concentrated invacuo. The residue partitioned between EtOAc and brine. The organiclayer was dried (MgSO₄) and concentrated in vacuo to give crude Part Ccompound as a yellow oil, which was used in the next step withoutfurther purification.

[0485] To a solution of crude Part C compound in CH₂Cl₂ (2 mL) was addedbenzoyl chloride (18 mg; 0.13 mmol) and Et₃N (10 μL). The solution wasstirred for 2 h at RT and then concentrated in vacuo. The residue wasdissolved in pyridine (5 mL) and stirred for 2 h at 80° C., then wascooled to RT and concentrated in vacuo to give crude Part D compound,which was used in the next step without further purification.

[0486] A solution of crude Part D compound in MeOH (2 mL) and aqueous 1N KOH (1 mL) was stirred for 2 h at RT and then was neutralized withaqueous 1 N HCl and concentrated in vacuo. The residue was purified byHPLC (YMC reverse-phase ODS 20×100 mm column; flow rate=20 mL/min; 10min continuous gradient from 30:70 B:A to 100% B+5 min hold-time at 100%B, where solvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1MeOH:H2O:TFA) to give the title Compound (5 mg; 7%)

[0487] [M+H]⁺=514.5

What is claimed is:
 1. A compound which has the structure

wherein m is 0, 1 or 2; n is 0, 1 or 2; Q is C or N A is (CH₂)_(x) wherex is 1 to 5 or A is (CH₂)_(x) where x¹ is 1 to 5 with an alkenyl bond oran alkynyl bond embedded anywhere in the chain, or A is —(CH₂)_(x)²—O—(CH₂)_(x) ³— where x² is 0 to 5 and x³ is 0 to 5, provided that atleast one of x² and x³ is other than 0; B is a bond or is (CH₂) where x⁴is 1 to 5; X is CH or N; X₂ is C, N, O or S; X₃ is C, N, O or S; X₄ isC, N, O or S; X₅ is C, N, O or S; X₆ is C, N, O or S; provided that atleast one of X₂, X₃, X₄ X₅ and X₆ is N; and at least one of X₂, X₃, X₄X₅ and X₆ is C, R¹ is H or alkyl; R² is H, alkyl, alkoxy, halogen, aminoor substituted amino or cyano; R^(2a), R^(2b) and R^(2c) may be the sameor different and are selected from H, alkyl, alkoxy, halogen, amino orsubstituted amino or cyano; R³ is selected from H, alkyl, arylalkyl,aryloxycarbonyl, alkyloxycarbonyl, alkynyloxycarbonyl,alkenyloxycarbonyl, arylcarbonyl, alkylcarbonyl, aryl, heteroaryl,cycloheteroalkyl, heteroarylcarbonyl, heteroaryl-heteroarylalkyl,alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino,alkoxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino,heteroaryl-heteroarylcarbonyl, alkylsulfonyl, alkenylsulfonyl,heteroaryloxycarbonyl, cycloheteroalkyloxycarbonyl, heteroarylalkyl,aminocarbonyl, substituted aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, heteroarylalkenyl, cycloheteroalkyl-heteroarylalkyl;hydroxyalkyl, alkoxy, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl,alkylaryloxycarbonyl, arylheteroarylalkyl, arylalkylarylalkyl,aryloxyarylalkyl, haloalkoxyaryloxycarbonyl,alkoxycarbonylaryloxycarbonyl, aryloxyaryloxycarbonyl,arylsulfinylarylcarbonyl, arylthioarylcarbonyl,alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl,heteroaryloxyarylalkyl, aryloxyarylcarbonyl,aryloxyarylalkyloxycarbonyl, arylalkenyloxycarbonyl, arylalkylcarbonyl,aryloxyalkyloxycarbonyl, arylalkylsulfonyl, arylthiocarbonyl,arylalkenylsulfonyl, heteroarylsulfonyl, arylsulfonyl, alkoxyarylalkyl,heteroarylalkoxycarbonyl, arylheteroarylalkyl, alkoxyarylcarbonyl,aryloxyheteroarylalkyl, heteroarylalkyloxyarylalkyl, arylarylalkyl,arylalkenylarylalkyl, arylalkoxyarylalkyl, arylcarbonylarylalkyl,alkylaryloxyarylalkyl, arylalkoxycarbonylheteroarylalkyl,heteroarylarylalkyl, arylcarbonylheteroarylalkyl,heteroaryloxyarylalkyl, arylalkenylheteroarylalkyl, arylaminoarylalkyl,aminocarbonylarylarylalkyl; Y is CO₂R⁴ where R⁴ is H or alkyl, or aprodrug ester, or Y is a C-linked 1-tetrazole, a phosphinic acid of thestructure P(O)(OR^(4a))R⁵ where R^(4a) is H or a prodrug ester, R⁵ isalkyl or aryl, or a phosphonic acid of the structure P(O)(OR^(4a))₂;(CH₂)_(x), (CH₂)_(x) ¹, (CH₂)_(x) ², (CH₂)_(x) ³, (CH₂)_(x) ⁴,(CH₂)_(m), and (CH₂)_(n) may be optionally substituted with 1, 2 or 3substituents; including all stereoisomers thereof, prodrug estersthereof, and pharmaceutically acceptable salts thereof, and specificallyexcluding the structure as shown below:

where X₂═N, X₃═C, X₄═O or S, Z═O or a bond
 2. The compound as defined inclaim 1 wherein X is CH.
 3. The compound as defined in claim 1 wherein Ais —(CH₂)_(x) ²—O—.
 4. The compound as defined in claim 1 wherein Q isC.
 5. The compound as defined in claim 1 wherein B is a bond.
 6. Thecompound as defined in claim 1 wherein


7. The compound as defined in claim 1 wherein R³ isarylalkyloxycarbonyl, arylheteroarylalkyl, aryloxyarylalkyl, arylalkyl,aryloxycarbonyl, haloaryloxycarbonyl, alkoxyaryloxycarbonyl,alkylaryloxycarbonyl, aryloxyaryloxycarbonyl, heteroaryloxyarylalkyl,heteroaryloxycarbonyl, aryloxyarylcarbonyl, arylalkenyloxycarbonyl,cycloalkylaryloxycarbonyl, arylalkylarylcarbonyl,heteroaryl-heteroarylalkyl, cycloalkyloxyaryloxycarbonyl,heteroaryl-heteroarylcarbonyl, arylalkylsulfonyl, arylalkenylsulfonyl,alkoxyarylalkyl, arylthiocarbonyl, cycloheteroalkylalkyloxycarbonyl,cycloheteroalkyloxycarbonyl, or polyhaloalkylaryloxycarbonyl, which maybe optionally substituted.
 8. The compound as defined in claim 1 whichthe structure


9. The compound as defined in claim 1 which has the structure


10. The compound as defined in claim 9 wherein R^(2a), R^(2b) and R^(2c)are each H; R¹ is alkyl, x² is 1 to 3; R² is H; m is 0 or (CH₂)_(m) isCH₂ or CHOH or CH-alkyl, X is C, X₂, X₃, X₄, X₅ and X₆ represent a totalof 1, 2 or 3 nitrogens, (CH₂)_(n) is a bond or CH₂ and R³ isalkoxyaryloxycarbonyl.
 11. The compound as defined in claim 10 whereinR¹ is CH₃ and R³ is methyloxyphenyloxycarbonyl.
 12. The compound asdefined in claim 1 wherein


13. The compounds as defined in claim 1 having the structure


14. A pharmaceutical composition comprising a compound as defined inclaim 1 and a pharmaceutically acceptable carrier therefor.
 15. A methodfor treating diabetes, Type 2 diabetes, and related diseases such asinsulin resistance, hyperglycemia, hyperinsulinemia, elevated bloodlevels of fatty acids or glycerol, hyperlipidemia, obesity,hypertriglyceridemia, inflammation, Syndrome X, diabetic complications,dysmetabolic syndrome, atherosclerosis, and related diseases, whichcomprises administgering to a patient in need of treatment atherapeutically effective amount of a compound as defined in claim 1.16. A method for treating early malignant lesions, ductal carcinoma insitu of the breast, lobular carcinoma in situ of the breast,premalignant lesions, fibroadenoma of the breast, prostaticintraepithelial neoplasia (PIN), liposarcomas and various otherepithelial tumors (including breast, prostate, colon, ovarian, gastricand lung), irritable bowel syndrome, Crohn's disease, gastric ulceritis,and osteoporosis and proliferative diseases such as psoriasis, whichcomprises administering to a patient in need of treatment atherapeutically effective amount of a compound as defined in claim 1.17. A pharmaceutical combination comprising a compound as defined inclaim 1 and a lipid-lowering agent, a lipid modulating agent, anantidiabetic agent, an anti-obesity agent, an antihypertensive agent, aplatelet aggregation inhibitor, and/or an antiosteoporosis agent. 18.The combination as defined in claim 17 wherein the antidiabetic agent is1, 2, 3 or more of a biguanide, a sulfonyl urea, a glucosidaseinhibitor, a PPARγ agonist, a PPAR α/γ dual agonist, an SGLT2 inhibitor,a DP4 inhibitor, an aP2 inhibitor, an insulin sensitizer, aglucagon-like peptide-1 (GLP-1), insulin and/or a meglitinide, theanti-obesity agent is a beta 3 adrenergic agonist, a lipase inhibitor, aserotonin (and dopamine) reuptake inhibitor, a thyroid receptor agonist,an aP2 inhibitor, a cannabinoid receptor-1 antagonist and/or ananorectic agent, the lipid lowering agent is an MTP inhibitor, an HMGCoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acidderivative, an upregulator of LDL receptor activity, a lipoxygenaseinhibitor, a farnesoid receptor (FXR) agonist, a liver X receptor (LXR)agonist, a CETP inhibitor or an ACAT inhibitor, the antihypertensiveagent is an ACE inhibitor, angiotensin II receptor antagonist, NEP/ACEinhibitor, calcium channel blocker and/or β-adrenergic blocker.
 19. Thecombination as defined in claim 18 wherein the antidiabetic agent is 1,2, 3 or more of metformin, glyburide, glimepiride, glipyride, glipizide,chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone,rosiglitazone, balaglitazone, insulin, Gl-262570, isaglitazone, JTT-501,NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide,KAD1129, AR-HO39242, GW-409544, KRP297, AZ-242, AC2993, LY315902, P32/98and/or NVP-DPP-728A, the anti-obesity agent is orlistat, ATL-962,AJ9677, L750355, CP331648, sibutramine, topiramate, axokine,dexamphetamine, phentermine, phenylpropanolamine, rimonabant (SR-141716)and/or mazindol, the lipid lowering agent is pravastatin, lovastatin,simvastatin, atorvastatin, fluvastatin, itavastatin, visastatin,rosuvastatin, pitavastatin, fenofibrate, gemfibrozil, clofibrate,avasimibe, ezetimibe, TS-962, MD-700, cholestagel, niacin and/orLY295427, the antihypertensive agent is an ACE inhibitor which iscaptopril, fosinopril, enalapril, lisinopril, quinapril, benazepril,fentiapril, ramipril or moexipril; an NEP/ACE inhibitor which isomapatrilat,[S[(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid (gemopatrilat) or CGS 30440; an angiotensin II receptor antagonistwhich is irbesartan, losartan, telmisartan or valsartan; amlodipinebesylate, prazosin HCl, verapamil, nifedipine, nadolol, propranolol,carvedilol, or clonidine HCl, the platelet aggregation inhibitor isaspirin, clopidogrel, ticlopidine, dipyridamole or ifetroban.